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Mucosal capillary thrombi in steroid refractory ulcerative colitis: Influence of low molecular weight heparin (LMWH) treatment
GASTROENTEROLOGY Vol. 118, No.4
A588 AGA ABSTRACTS
3050
3052
INFLIXIMAB FOR TREATMENT OF PERINEAL METASTATIC CROHN'S DISEASE. Klaas van der Linde, Maarten A. Meijssen, Ad A. van Bodegraven, Ruud A. van Hogezand, Stephan J. Marks, Daan W. Hommes, Sander 1. van
CLINICAL EFFECT ON ULCERATIVE COLITIS WITH DIETARY SUPPLEMENTATION BY 0-3 FATTY ACIDS; A DOUBLE BLIND, RANDOMISED STUDY.
Deventer, Univ Hosp Rotterdam, Rotterdam, Netherlands; Westeinde Hosp, The Hague, Netherlands; Free Univ Hosp, Amsterdam, Netherlands; Leiden Univ Med Ctr, Leiden, Netherlands; Centocor B V, Leiden, Netherlands; Acad Med Ctr, Amsterdam, Netherlands. Background Proctocolectomy may be necessary in patients with severe therapy-resistant perineal Crohn' s disease (CD). Afterwards noncaseating granulomatous inflammation may persist, leading to perineal defects, abscesses and fistulas non-contiguous with the gastrointestinal tract. Surgical and medical management of this 'metastatic Crohn's disease' (MCD) is difficult and often unsuccessful. Recently, infliximab a chimeric monoclonal antibody to human tumor necrosis factor a showed to be a potent immunomodulatory agent for treatment of perianal fistulas in CD. I Whether infliximab is therapeutic also in patients with MCD is not clear. So far, only two cases have been described, both of which demonstrated a clinical response? Methods Medical records were reviewed of Dutch patients with clinically proven MCD, who were treated with infliximab according to the national multi-center open label expanded access treatment program of infliximab. This study started in January 1999. Infliximab was administered as an intravenous infusion in a dose of 5 mglkg at week 0, 2 and 6. Results We identified 7 patients with severe therapy-resistant MCD. Six of them were female. The mean age was 36 years (range 27-53 years). CD was diagnosed at a mean age of 22 years (range 10-37 years). All but one patient had undergone total proctocolectomy with an ileostomy. One patient had a subtotal proctocolectomie with a right-sided colostomy. Current metastatic lesions included fistulas of the perineum (n =6), vulval vagina (n=3), groin (n=I), and upper leg (n=1). Also larger perineal ulcerative defects (n=3) appeared. Concomitant medication included 5-ASA (n=2), tacrolimus (n=2), and azathioprine (n= I). The mean follow-up after starting infliximab was 22 weeks (range 10-33 weeks). At the end of treatment only 2 patients experienced a partial response, including less pain and/or drainage of the fistulas. One used tacrolimus, the other 5-ASA and azathioprine. Because of recurrent symptoms, both patients were treated again with the same result. Adverse events were reported in 2 patients. One experienced malaise and nausea. The other was diagnosed with an otitis media. Conclusion This small observational study demonstrates that infliximab may be less effective in patients with MCD compared to CD. Because of inconsistencies between our results and previously published data", studies in a larger patient population are warranted. References I Present DH, et al. N Engl J Med 1999; 340: 1398-1405. 2 Dullemen HM, et al. Dis Colon Rectum 1998; 41: 98-102.
3051 EFFICACY AND SAFETY OF INFLIXIMAB TREATMENT FOR REFRACTORY AND FISTULIZING CROHN'S DISEASE IN A DUTCH EXPANDED ACCESS PROGRAM. Ruud A. van Hogezand, Maurice G. Russel, Anton Naber, Bas Oldenburg, Ad A. Bodegraven, Hendrik M. van Dullemen, Maarten A. Meijssen, Eva Hurek, Tom Schaible, Stephan J. Marks, Sander 1. van Deventer, Leiden Univ Med Ctr, Leiden, Netherlands; Univ Hosp Maastricht, Maastricht, Netherlands; Univ Hosp Nijmegen, Nijmegen, Netherlands; Univ Hosp Utrecht, Utrecht, Netherlands; Free Univ Hosp, Amsterdam, Netherlands; Univ Hosp Groningen, Groningen, Netherlands; Univ Hosp Rotterdam, Rotterdam, Netherlands; Schering-Plough B V, Maarssen, Netherlands; Centocor, Malvern, PA; Centocor B V, Leiden, Netherlands; Acad Med Ctr, Amsterdam, Netherlands. Background: Randomized trials have shown the beneficial effect of antiTNFa antibody infliximab (Remicade''Y) in active refractory and fistulizing Crohn's disease. Aim: To investigate the efficacy and safety of infliximab in a Dutch cohort of active refractory or fistulizing Crohn' s disease patients at 8 university and 5 peripheral hospitals through an open-label expanded access program. Methods: One-hundred twenty-six patients were included. 49 with active Crohn's disease (CD) received a single infusion of 5 mglkg infliximab, 77 with fistulizing Crohn's disease received three infusions at week 0, 2 and 6. One retreatment was permitted between 8 and 14 weeks after the last infusion, up to the discretion of the physician. Follow-up was 12-14 weeks after the last infusion with an additional 12-14 weeks for retreated patients. The duration of response and the effect of concomitant immunomodulation are under study. Results: Preliminary data from the first 25 patients have been analyzed. The median CDAI in the CD group (n= 11) dropped from 315 to 125 at week 4, in the fistulizing group (n=9) from 153 to 47 at week 6. The number of patients into remission (CDAI<150) was 6/11 in the CD group at week 4 and 8/9 in the fistulizing group at week 6. The median IBDQ in the CD group (n=13) increased from 128 to 185 at week 4, in the fistulizing group (n=12) from 147 to 179 at week 6. A full analysis for all efficacy and safety parameters of all patients will be available May 2000. Conclusion: These preliminary results confirm the efficacy of infliximab in a Dutch cohort of patients with active refractory and fistulizing Crohn's disease.
T. J. Varghese, D. Coomansingh, S. Richardson, N. A. Mowat, P. W. Brunt, A. ElTahir, O. Eremin, Dept of Surg, Univ of Aberdeen and Nottingham, Nottingham, United Kingdom; Dept of Gastroenterology, Univ of Aberdeen, Aberdeen, United Kingdom; Dept of Surg, Univ of Aberdeen, Aberdeen, United Kingdom; Dept of Surg, Univ of Nottimgham, Nottingham, United Kingdom. INTRODUCTION. Incidence of colitis is high in N.E. Scotland. Essential fatty acids (EFAs) have previously been shown to have beneficial effects in distal proctocolitis. AIM. Therefore, in a double blind randomised study, patients with active colitis, not treated with immunosuppressants, were studied and the clinical efficacy of EFAs evaluated. METHODS. Patients (n=29) receiving standard therapy, received either placebo (sunflower oil) or supplementation with w-3 EFAs (5.6grn/d) for six months. Patients were assessed at the start of therapy, three months later and end of the study period (six months). Extent of disease (I = proctitis 2=proctosigmoiditis 3= left sided colitis 4 = subtotal colitis 5= total colitis), colonoscopy (1-7), histogy (0-4) and clinical (1-32) scores were used to assess the severity of the disease. RESULTS. There was disease improvement in both groups but more significantly in the group receiving the EFAs. In particular, there was significant improvement in the clinical and histological scores in the EFA group. EFAs was well tolerated and produced minimal side effects. CONCLUSION. In order to improve upon present immunosuppressive therapy, non-tissue damaging therapy needs to be introduced and EFAs may be such a promising approach to control this difficult to treat disease.
Clinical Score Month 0 Month 3 Month 6 Colonoscoplc Score Month 0 Month 6 Histology Score Month 0 Month 6
Mean Score (Placebo n=17)
SEM
Mean Score (EFAs n=12)
SEM
P Value (MannWhitney UTest)
10.82 6.34 7.41
0.65 0.66 0.81
11.17 525 4.42
098 0.90 091
0024
3.81 2.94
0.26 0.37
367 2.25
022 0.48
0.328
324 265
0.16 0.26
325 150
0.18 0.26
0.008
3053 MUCOSAL CAPILLARY THROMBI IN STEROID REFRACTORY ULCERATIVE COLITIS: INFLUENCE OF LOW MOLECULAR WEIGHT HEPARIN (LMWH) TREATMENT. Anton A. Vrji, Jeroen M. Jansen, Adriaan de Bruine, Reinhold W. Stockbrugger, Departments of Gastroenterology and Pathology, University Hospital Maastricht, Maastricht, The Netherlands. Introduction and aims In ulcerative colitis (UC) the occurrence of mucosal microvascular thrombosis has been demonstrated in rectal biopsies. Some of these patients improved when they were treated for concomitant thromboembolic disease with heparin. We studied the clinical effectivity as well as the influence on microthrombi of additional LMWH treatment in patients with active UC, refractory to 5-ASA and steroids. Patients and methods In an open, prospective study patients were treated for at least 8 weeks with LMWH. Twenty-three patients with UC received nadroparine (Fraxiparin'") 15000 anti-Xa IC-U/ml bid. subcutaneously, during a flare-up of UC while tapering steroids. The median age was 50 yrs (min-max: 8-85) , the male/female ratio was 14 to 9. The median dose of oral prednisolone at the time of flare-up and the start of nadroparine was 20 mg (10-30 mg). Before and after nadroparine treatment, the clinical (Colitis Activity Index or CAl) and biochemical (ESR, CRP) response was determined. In 14 patients rectosigmoideal biopsies were studied on histologic inflammatory characteristics (HDA score from 0 to 12) as well as the presence of microvascular thrombi by anti-fibrin antibodies (Dako Ltd. UK). Results In 3 patients, nadroparine was withdrawn after 2 weeks because of a 3-fold rise in liver aminotransferase levels in 2 and persistent rectal blood loss in one patient. Twenty of 23 patients had a good clinical and biochemical reponse. The endoscopic extension was unchanged in 15 patients, worsened in I and improved in 4. In 14 patients, the mean HDA score reduced from 6.7 to 3.8 (p=O.OOI), and in all patients microvascular thrombi could be detected in the biopsies at entry. However, although the mean number of fibrin-thrombi per 3 mm biopsy reduced from 27.0 to 14.0, the difference was not significant (p=0.280). Also, the presence of microvascular thrombi did not correlate with the CAlor HDA score. Conclusions In steroid refractory UC microvascular thrombi could easily be demonstrated. Although the result of LMWH use in UC is clinically promising, the reduction of (histologic) inflammation was not accompanied by a significant reduction of the number of microvascular thrombi after 8 weeks of anti-thrombotic treatment. The study confirms the presence of a chronic hypercoagulative disease state in UC.
A588 AGA ABSTRACTS
3050
3052
INFLIXIMAB FOR TREATMENT OF PERINEAL METASTATIC CROHN'S DISEASE. Klaas van der Linde, Maarten A. Meijssen, Ad A. van Bodegraven, Ruud A. van Hogezand, Stephan J. Marks, Daan W. Hommes, Sander 1. van
CLINICAL EFFECT ON ULCERATIVE COLITIS WITH DIETARY SUPPLEMENTATION BY 0-3 FATTY ACIDS; A DOUBLE BLIND, RANDOMISED STUDY.
Deventer, Univ Hosp Rotterdam, Rotterdam, Netherlands; Westeinde Hosp, The Hague, Netherlands; Free Univ Hosp, Amsterdam, Netherlands; Leiden Univ Med Ctr, Leiden, Netherlands; Centocor B V, Leiden, Netherlands; Acad Med Ctr, Amsterdam, Netherlands. Background Proctocolectomy may be necessary in patients with severe therapy-resistant perineal Crohn' s disease (CD). Afterwards noncaseating granulomatous inflammation may persist, leading to perineal defects, abscesses and fistulas non-contiguous with the gastrointestinal tract. Surgical and medical management of this 'metastatic Crohn's disease' (MCD) is difficult and often unsuccessful. Recently, infliximab a chimeric monoclonal antibody to human tumor necrosis factor a showed to be a potent immunomodulatory agent for treatment of perianal fistulas in CD. I Whether infliximab is therapeutic also in patients with MCD is not clear. So far, only two cases have been described, both of which demonstrated a clinical response? Methods Medical records were reviewed of Dutch patients with clinically proven MCD, who were treated with infliximab according to the national multi-center open label expanded access treatment program of infliximab. This study started in January 1999. Infliximab was administered as an intravenous infusion in a dose of 5 mglkg at week 0, 2 and 6. Results We identified 7 patients with severe therapy-resistant MCD. Six of them were female. The mean age was 36 years (range 27-53 years). CD was diagnosed at a mean age of 22 years (range 10-37 years). All but one patient had undergone total proctocolectomy with an ileostomy. One patient had a subtotal proctocolectomie with a right-sided colostomy. Current metastatic lesions included fistulas of the perineum (n =6), vulval vagina (n=3), groin (n=I), and upper leg (n=1). Also larger perineal ulcerative defects (n=3) appeared. Concomitant medication included 5-ASA (n=2), tacrolimus (n=2), and azathioprine (n= I). The mean follow-up after starting infliximab was 22 weeks (range 10-33 weeks). At the end of treatment only 2 patients experienced a partial response, including less pain and/or drainage of the fistulas. One used tacrolimus, the other 5-ASA and azathioprine. Because of recurrent symptoms, both patients were treated again with the same result. Adverse events were reported in 2 patients. One experienced malaise and nausea. The other was diagnosed with an otitis media. Conclusion This small observational study demonstrates that infliximab may be less effective in patients with MCD compared to CD. Because of inconsistencies between our results and previously published data", studies in a larger patient population are warranted. References I Present DH, et al. N Engl J Med 1999; 340: 1398-1405. 2 Dullemen HM, et al. Dis Colon Rectum 1998; 41: 98-102.
3051 EFFICACY AND SAFETY OF INFLIXIMAB TREATMENT FOR REFRACTORY AND FISTULIZING CROHN'S DISEASE IN A DUTCH EXPANDED ACCESS PROGRAM. Ruud A. van Hogezand, Maurice G. Russel, Anton Naber, Bas Oldenburg, Ad A. Bodegraven, Hendrik M. van Dullemen, Maarten A. Meijssen, Eva Hurek, Tom Schaible, Stephan J. Marks, Sander 1. van Deventer, Leiden Univ Med Ctr, Leiden, Netherlands; Univ Hosp Maastricht, Maastricht, Netherlands; Univ Hosp Nijmegen, Nijmegen, Netherlands; Univ Hosp Utrecht, Utrecht, Netherlands; Free Univ Hosp, Amsterdam, Netherlands; Univ Hosp Groningen, Groningen, Netherlands; Univ Hosp Rotterdam, Rotterdam, Netherlands; Schering-Plough B V, Maarssen, Netherlands; Centocor, Malvern, PA; Centocor B V, Leiden, Netherlands; Acad Med Ctr, Amsterdam, Netherlands. Background: Randomized trials have shown the beneficial effect of antiTNFa antibody infliximab (Remicade''Y) in active refractory and fistulizing Crohn's disease. Aim: To investigate the efficacy and safety of infliximab in a Dutch cohort of active refractory or fistulizing Crohn' s disease patients at 8 university and 5 peripheral hospitals through an open-label expanded access program. Methods: One-hundred twenty-six patients were included. 49 with active Crohn's disease (CD) received a single infusion of 5 mglkg infliximab, 77 with fistulizing Crohn's disease received three infusions at week 0, 2 and 6. One retreatment was permitted between 8 and 14 weeks after the last infusion, up to the discretion of the physician. Follow-up was 12-14 weeks after the last infusion with an additional 12-14 weeks for retreated patients. The duration of response and the effect of concomitant immunomodulation are under study. Results: Preliminary data from the first 25 patients have been analyzed. The median CDAI in the CD group (n= 11) dropped from 315 to 125 at week 4, in the fistulizing group (n=9) from 153 to 47 at week 6. The number of patients into remission (CDAI<150) was 6/11 in the CD group at week 4 and 8/9 in the fistulizing group at week 6. The median IBDQ in the CD group (n=13) increased from 128 to 185 at week 4, in the fistulizing group (n=12) from 147 to 179 at week 6. A full analysis for all efficacy and safety parameters of all patients will be available May 2000. Conclusion: These preliminary results confirm the efficacy of infliximab in a Dutch cohort of patients with active refractory and fistulizing Crohn's disease.
T. J. Varghese, D. Coomansingh, S. Richardson, N. A. Mowat, P. W. Brunt, A. ElTahir, O. Eremin, Dept of Surg, Univ of Aberdeen and Nottingham, Nottingham, United Kingdom; Dept of Gastroenterology, Univ of Aberdeen, Aberdeen, United Kingdom; Dept of Surg, Univ of Aberdeen, Aberdeen, United Kingdom; Dept of Surg, Univ of Nottimgham, Nottingham, United Kingdom. INTRODUCTION. Incidence of colitis is high in N.E. Scotland. Essential fatty acids (EFAs) have previously been shown to have beneficial effects in distal proctocolitis. AIM. Therefore, in a double blind randomised study, patients with active colitis, not treated with immunosuppressants, were studied and the clinical efficacy of EFAs evaluated. METHODS. Patients (n=29) receiving standard therapy, received either placebo (sunflower oil) or supplementation with w-3 EFAs (5.6grn/d) for six months. Patients were assessed at the start of therapy, three months later and end of the study period (six months). Extent of disease (I = proctitis 2=proctosigmoiditis 3= left sided colitis 4 = subtotal colitis 5= total colitis), colonoscopy (1-7), histogy (0-4) and clinical (1-32) scores were used to assess the severity of the disease. RESULTS. There was disease improvement in both groups but more significantly in the group receiving the EFAs. In particular, there was significant improvement in the clinical and histological scores in the EFA group. EFAs was well tolerated and produced minimal side effects. CONCLUSION. In order to improve upon present immunosuppressive therapy, non-tissue damaging therapy needs to be introduced and EFAs may be such a promising approach to control this difficult to treat disease.
Clinical Score Month 0 Month 3 Month 6 Colonoscoplc Score Month 0 Month 6 Histology Score Month 0 Month 6
Mean Score (Placebo n=17)
SEM
Mean Score (EFAs n=12)
SEM
P Value (MannWhitney UTest)
10.82 6.34 7.41
0.65 0.66 0.81
11.17 525 4.42
098 0.90 091
0024
3.81 2.94
0.26 0.37
367 2.25
022 0.48
0.328
324 265
0.16 0.26
325 150
0.18 0.26
0.008
3053 MUCOSAL CAPILLARY THROMBI IN STEROID REFRACTORY ULCERATIVE COLITIS: INFLUENCE OF LOW MOLECULAR WEIGHT HEPARIN (LMWH) TREATMENT. Anton A. Vrji, Jeroen M. Jansen, Adriaan de Bruine, Reinhold W. Stockbrugger, Departments of Gastroenterology and Pathology, University Hospital Maastricht, Maastricht, The Netherlands. Introduction and aims In ulcerative colitis (UC) the occurrence of mucosal microvascular thrombosis has been demonstrated in rectal biopsies. Some of these patients improved when they were treated for concomitant thromboembolic disease with heparin. We studied the clinical effectivity as well as the influence on microthrombi of additional LMWH treatment in patients with active UC, refractory to 5-ASA and steroids. Patients and methods In an open, prospective study patients were treated for at least 8 weeks with LMWH. Twenty-three patients with UC received nadroparine (Fraxiparin'") 15000 anti-Xa IC-U/ml bid. subcutaneously, during a flare-up of UC while tapering steroids. The median age was 50 yrs (min-max: 8-85) , the male/female ratio was 14 to 9. The median dose of oral prednisolone at the time of flare-up and the start of nadroparine was 20 mg (10-30 mg). Before and after nadroparine treatment, the clinical (Colitis Activity Index or CAl) and biochemical (ESR, CRP) response was determined. In 14 patients rectosigmoideal biopsies were studied on histologic inflammatory characteristics (HDA score from 0 to 12) as well as the presence of microvascular thrombi by anti-fibrin antibodies (Dako Ltd. UK). Results In 3 patients, nadroparine was withdrawn after 2 weeks because of a 3-fold rise in liver aminotransferase levels in 2 and persistent rectal blood loss in one patient. Twenty of 23 patients had a good clinical and biochemical reponse. The endoscopic extension was unchanged in 15 patients, worsened in I and improved in 4. In 14 patients, the mean HDA score reduced from 6.7 to 3.8 (p=O.OOI), and in all patients microvascular thrombi could be detected in the biopsies at entry. However, although the mean number of fibrin-thrombi per 3 mm biopsy reduced from 27.0 to 14.0, the difference was not significant (p=0.280). Also, the presence of microvascular thrombi did not correlate with the CAlor HDA score. Conclusions In steroid refractory UC microvascular thrombi could easily be demonstrated. Although the result of LMWH use in UC is clinically promising, the reduction of (histologic) inflammation was not accompanied by a significant reduction of the number of microvascular thrombi after 8 weeks of anti-thrombotic treatment. The study confirms the presence of a chronic hypercoagulative disease state in UC.