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W1283 Infliximab Monotherapy vs. Combined Infliximab-Immunomodulator Therapy in Ulcerative Colitis
AGA Abstracts
with MTX, 1.2 [0-9.4] with AZA (P = 0.003 vs MTX) and 1.1 [0-23.6] with IFX (N.S. vs MTX). Median SES-CD was 6.5 [2-18] with MTX, 3 [0-16] with AZA (P = 0.01 vs MTX) and 2 [0-27] with IFX (P = 0.035 vs MTX). Conclusion: Sustained clinical remission of CD with MTX is associated with a lower rate of MH when compared to AZA or IFX. MTX provides incomplete healing of the gut mucosa which may explain the high relapse rate of CD when given as maintenance.
sigmoid colon. Total RNA was extracted from mucosal samples and quantitative expression of 96 inflammation-related genes was evaluated by qPCR, by means of TaqMan Low Density Array Human Immune Panel (Applied Biosystems, Foster City, CA). Mucosal gene expression was evaluated before and after therapy, and compared with results obtained from 16 controls with normal-appearing mucosa (6M, median age 38 yrs, range 20-44). Results. Among the panel of 96 inflammation-related genes, 36 were found to be significantly upregulated in the colonic mucosa of patients with active IBD in comparison to controls. As compared to baseline, 6 weeks therapy with infliximab induced a significant downregulation of the expression of interleukin(IL)-17A (relative expression: 0.72 vs. 0.10 at T0 and T6, respectively), IL-1β (20.55 vs. 3.30), IL-1α (10.65 vs. 0.50), IL-6 (1.11 vs. 0.20), IL-8 (55.24 vs. 1.92) and NOS2A (86.74 vs. 16.75) (all P<0.05). In the CD patients subgroup, TNFα neutralization led to a reduced expression of the Th1 cytokines interferon-gamma (IFN-γ) and lymphotoxin-α, and to an upregulation of the expression of IL-4. With the exception of IL-8 and NOS2A, no significant differences were observed between the post-therapy levels of the above-mentioned genes and those measured in controls. Conclusions. Our data demonstrate that TNFα neutralization by infliximab induces a rapid normalization of several inflammation-related genes, including the signature Th1 and Th17-cytokines IFN-γ and IL17A. These results provide further insights on the mechanisms of anti-TNF agents in controlling mucosal inflammation.
W1280 Use of Immunosuppressants and Anti-TNF for Inflammatory Bowel Diseases (IBD) in Current Practice: Data From a French Regional Survey David Laharie, Anne-Marie Leveque, Christophe Barberis, Maylis Capdepont, Richard Beyssac, Frank Zerbib Introduction: Medical treatment of IBD patients has dramatically changed during the last decade with the large diffusion of immunosuppressants (IS) and development of biologics. This recent evolution could have induced therapeutic discrepancies between GI-practitioners. Aim: to describe the use of immunosuppressants and anti-TNF in a regional survey. . Patients & Methods: From October 2008 et March 2009, all adults with IBD resident in the Région Aquitaine (south western France; 3.1 millions inhabitants) were consecutively included when they met a GI-practitioner working in the area. Investigators were divided into three groups according to the number of patients enrolled: <6 cases (i.e. <1/month), from 6 to 26 (between 1/week and 1/month), >26 (>1/week). Use of azathioprine/6-mercaptopurine (AZA/6-MP)and anti-TNF was studied separately between Crohn's disease (CD) and ulcerative colitis (UC) in uni- and multivariate analysis. Results: The 92 GI-practitioners included 1158 IBD patients: 676 CD - including 619 with severe disease -, 412 UC - including 315 with severe disease - and 46 undetermined IBD. Within the 92 investigators, 46% enrolled <6 cases (10.3% of patients), 40 6-26 cases (37.3%) and 6 >6 cases (52.4%). According to the number of patients recruited by investigator (<6, 6-26, >26), the proportions of patients with severe CD treated were 61%, 63% and 73% for AZA/6-MP (p=0.021) and 18%, 23% and 48% for anti-TNF (p<0.001). In UC, they were 37%, 34% and 62% for AZA/6-MP (p<0.001) and 0%, 3% and 28% for infliximab ((p<0.001). Conclusion: In patients with severe CD, AZA/ 6-MP is used by most of the French GI-practitioners. Others immunosuppressants and antiTNF are restricted to GI-practitioners involved in IBD. Regional networks could homogenize medical treatments in patients with severe IBD.
W1283 Infliximab Monotherapy vs. Combined Infliximab-Immunomodulator Therapy in Ulcerative Colitis Yelena Zadvornova, Ashwin N. Ananthakrishnan, Daniel J. Stein, Susan Skaros, Kathryn Johnson, Amar S. Naik, Lilani P. Perera, Mazen Issa Introduction:Combined immunomodulator (IMM) and biologic therapy is superior to IMM or biologic therapy (Infliximab, IFX) alone in IMM naïve Crohn's disease (CD) patients (SONIC trial). The potential benefit of combination therapy in patients with Ulcerative Colitis (UC) has not been adequately defined. The aim of our study was to examine whether the outcomes of UC patients initiated on IFX differed by use of combination therapy. Methods: This single center retrospective study included all UC outpatients initiated on IFX maintenance therapy after the 0, 2,and 6 week induction dosing. Information on demographics, disease extent, age of diagnosis and duration of disease, smoking status, and type of medical therapy was obtained from our database. Combined IMM therapy included azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate (MTX). Our primary outcome was occurrence of IFX discontinuation and/or colectomy. For patients able to continue maintenance therapy, duration of IFX treatment was calculated. Cox proportional hazards model was used to identify if combined IMM therapy influenced occurrence of our primary outcome. Results: A total of 104 UC patients were included in our study; 59 patients (57%) were on combination IMM therapy while 44 patients (43%) were on IFX alone. There was no difference in disease duration at IFX initiation (66 months vs. 74 months, p=0.63), sex or extent of disease between the two groups. The proportion of patients with treatment interruption (10% vs. 7%) was also similar between the two groups. The primary outcome occurred in 18 patients in the combined IMM (31%) and 18 patients in the IFX alone group (40%, p=0.31). Ten patients (17%) in the combined IMM and 8 patients (18%) in the IFX alone group underwent colectomy (p=0.91). On multivariate analysis, combined IMM therapy was not predictive of IFX discontinuation or colectomy (Hazard ratio (HR) 1.22, 95% CI 0.54-2.76). Subgroup analysis by IMM type (AZA/6-MP vs. MTX) showed similar outcomes in both groups. Reasons for IFX discontinuation differed between the two groups. Discontinuation due to infusion reaction or drug intolerance was seen in 18% of patients treated with IFX alone compared to only 3% in the combined IMM group (p=0.014). Conclusion: Combination IMM therapy did not influence drug discontinuation or colectomy in UC patients treated with IFX in our single center cohort. Combination therapy was associated with significantly lower likelihood of drug discontinuation due to intolerance or infusion reactions.
W1281 The Phase I Safety and Feasibility Results of Autologous Intravenous Mesenchymal Stromal Cell Treatment in Refractory Crohn's Disease Marjolijn Duijvestein, Manon E. Wildenberg, Barbara B. Wendrich, Anne Christine W. Vos, Auke Verhaar, Herma H. Fidder, Helene Roelofs, Jaap Jan Zwaginga, Willem E. Fibbe, Gijs R. van den Brink, Daniel W. Hommes BACKGROUND Mesenchymal Stromal Cell (MSC) transplantation is being explored as therapy for various indications, including graft versus host disease, myocardial infarction and Crohn's Disease (CD). AIM The aim of this study was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory CD. METHODS Nine adult patients (7 females/2 males) with a median baseline CD activity index (CDAI) score of 317 (224-378) underwent bone marrow aspiration under local anesthesia. Mononuclear cells were isolated and MSCs were expanded and tested for phenotype and functionality In Vitro. Patients received 2 doses of 1-2x10^6 cells/kg bodyweight, intravenously, 7 days apart. Primary outcomes were feasibility and safety of autologous MSC expansion and infusion. Effects on CDAI were recorded as secondary outcome. RESULTS MSC isolated from CD patients showed similar morphology, phenotype and growth potential as those of healthy donors. Moreover, similar differentiation along the adipogenic and osteogenic lineages and In Vitro immunomodulatory capacity was observed, as both healthy donor and CD MSC reduced lymphocyte proliferation up to 70%. MSC infusion was successful and without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. The first patient was a chronic severe steroid refractory patient on the waiting list for surgery. Despite an initial drop in CDAI, she was operated upon due to poor general condition and persistent rectal blood loss before primary endpoint was met. The other patients showed a decrease in median CDAI of 59 points 6 weeks post transplant. Endoscopic improvement was seen in two patients with extensive CD localized in the colon whereas no significant improvement was seen in two patients with ileal CD. CONCLUSIONS Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory CD, no serious adverse events were detected during harvesting and study follow up. In addition, possible clinical and endoscopic efficacy was observed.
W1284 The Manitoba IBD Cohort Study: Longitudinal use of Complementary and Alternative Medicine (CAM) in IBD Over 54 Months Patricia Rawsthorne, Kylie I. Bernstein, Rachel Carr, Lesley A. Graff, John R. Walker, Norine Miller, Linda Rogala, Charles N. Bernstein There has been increased and widespread use of CAM in general and for IBD. We aimed to determine the prevalence of CAM use over time in a population-based cohort of IBD patients. Methods: The Manitoba IBD Cohort Study is a longitudinal, population-based study of multiple determinants of health outcomes in those diagnosed with IBD within 7 years at enrolment (mean disease duration=4 years). Participants completed semi-annual selfadministered questionnaires, and participated in annual in-person interviews starting at month 0 to month 54. The questionnaires inquired about use of 13 CAM service providers and 10 CAM products in months 0, 12, 30 and 54; and whether the CAM use was in relation to their IBD in months 12, 30 and 54. Additional services or products were captured under the “Other” category. Results: Approximately 40% of subjects used CAM over the 54 months. Females (n=226) consistently used more CAM than males (n=153) after month 0 (p<0.004). There was no significant difference between subjects with Crohn's (n=186) vs UC (n=193) in use. The most often used services (on average) were massage therapy (21%), chiropractor (10%) and Naturopath/Homeopath/Herbalist (4%). The most often used CAM products were Lactobacillus/acidophilus (6%), fish oils (3%), chamomile (2.7%) and glucosamine (2.5%). 45 subjects used any form of CAM in each time point (14%). 75 subjects (23%) never used any form of CAM in any time point. Conclusions: IBD subjects try CAM quite commonly (77% at some time) although only 14% remain consistent users over a period of 4.5 years. Nearly 40% of users use it for their IBD so the majority use it for other issues. Since its use is so common clinicians need to make a bigger effort in understanding why subjects choose it, where they feel it benefits them and consider whether there are adverse interactions with the management they are prescribing. CAM use over time (all data are in %)
W1282 Infliximab Modulates Mucosal Cytokine Profile in Patients With Inflammatory Bowel Diseases Flavio Caprioli, Francesca Bosè, Lorenzo Raeli, Chiara Viganò, Guido Basilisco, Dario Conte, Sergio Abrignani, Eva Reali Background and aims. Monoclonal antibodies against tumor necrosis factor-alpha (TNFα) are highly effective in the treatment of patients with inflammatory bowel diseases (IBD), even if their mechanism of action has yet to be fully elucidated. In patients with psoriasis, TNFα neutralization has been associated with a reduced dermal expression of proinflammatory cytokines produced by Th1 and Th17 lymphocytes, T cell lineages critically involved also in the pathogenesis of IBD. In this study, we aimed to evaluate the effect of TNFα neutralization by infliximab in modulating mucosal cytokine profile in patients with IBD. Patients and methods. Twelve patients with active left-sided colonic IBD (6 patients with Crohn's disease (CD) and 6 with ulcerative colitis, 7M, median age 34 yrs, range 25-50), and naïve to anti-TNF therapy were enrolled in the study. All patients underwent induction therapy with infliximab (5 mg/kg, administered at week 0, 2 and 6). At enrolment and at week 6 a sigmoidoscopy was performed, and mucosal samples were obtained from the
AGA Abstracts
S-690
with MTX, 1.2 [0-9.4] with AZA (P = 0.003 vs MTX) and 1.1 [0-23.6] with IFX (N.S. vs MTX). Median SES-CD was 6.5 [2-18] with MTX, 3 [0-16] with AZA (P = 0.01 vs MTX) and 2 [0-27] with IFX (P = 0.035 vs MTX). Conclusion: Sustained clinical remission of CD with MTX is associated with a lower rate of MH when compared to AZA or IFX. MTX provides incomplete healing of the gut mucosa which may explain the high relapse rate of CD when given as maintenance.
sigmoid colon. Total RNA was extracted from mucosal samples and quantitative expression of 96 inflammation-related genes was evaluated by qPCR, by means of TaqMan Low Density Array Human Immune Panel (Applied Biosystems, Foster City, CA). Mucosal gene expression was evaluated before and after therapy, and compared with results obtained from 16 controls with normal-appearing mucosa (6M, median age 38 yrs, range 20-44). Results. Among the panel of 96 inflammation-related genes, 36 were found to be significantly upregulated in the colonic mucosa of patients with active IBD in comparison to controls. As compared to baseline, 6 weeks therapy with infliximab induced a significant downregulation of the expression of interleukin(IL)-17A (relative expression: 0.72 vs. 0.10 at T0 and T6, respectively), IL-1β (20.55 vs. 3.30), IL-1α (10.65 vs. 0.50), IL-6 (1.11 vs. 0.20), IL-8 (55.24 vs. 1.92) and NOS2A (86.74 vs. 16.75) (all P<0.05). In the CD patients subgroup, TNFα neutralization led to a reduced expression of the Th1 cytokines interferon-gamma (IFN-γ) and lymphotoxin-α, and to an upregulation of the expression of IL-4. With the exception of IL-8 and NOS2A, no significant differences were observed between the post-therapy levels of the above-mentioned genes and those measured in controls. Conclusions. Our data demonstrate that TNFα neutralization by infliximab induces a rapid normalization of several inflammation-related genes, including the signature Th1 and Th17-cytokines IFN-γ and IL17A. These results provide further insights on the mechanisms of anti-TNF agents in controlling mucosal inflammation.
W1280 Use of Immunosuppressants and Anti-TNF for Inflammatory Bowel Diseases (IBD) in Current Practice: Data From a French Regional Survey David Laharie, Anne-Marie Leveque, Christophe Barberis, Maylis Capdepont, Richard Beyssac, Frank Zerbib Introduction: Medical treatment of IBD patients has dramatically changed during the last decade with the large diffusion of immunosuppressants (IS) and development of biologics. This recent evolution could have induced therapeutic discrepancies between GI-practitioners. Aim: to describe the use of immunosuppressants and anti-TNF in a regional survey. . Patients & Methods: From October 2008 et March 2009, all adults with IBD resident in the Région Aquitaine (south western France; 3.1 millions inhabitants) were consecutively included when they met a GI-practitioner working in the area. Investigators were divided into three groups according to the number of patients enrolled: <6 cases (i.e. <1/month), from 6 to 26 (between 1/week and 1/month), >26 (>1/week). Use of azathioprine/6-mercaptopurine (AZA/6-MP)and anti-TNF was studied separately between Crohn's disease (CD) and ulcerative colitis (UC) in uni- and multivariate analysis. Results: The 92 GI-practitioners included 1158 IBD patients: 676 CD - including 619 with severe disease -, 412 UC - including 315 with severe disease - and 46 undetermined IBD. Within the 92 investigators, 46% enrolled <6 cases (10.3% of patients), 40 6-26 cases (37.3%) and 6 >6 cases (52.4%). According to the number of patients recruited by investigator (<6, 6-26, >26), the proportions of patients with severe CD treated were 61%, 63% and 73% for AZA/6-MP (p=0.021) and 18%, 23% and 48% for anti-TNF (p<0.001). In UC, they were 37%, 34% and 62% for AZA/6-MP (p<0.001) and 0%, 3% and 28% for infliximab ((p<0.001). Conclusion: In patients with severe CD, AZA/ 6-MP is used by most of the French GI-practitioners. Others immunosuppressants and antiTNF are restricted to GI-practitioners involved in IBD. Regional networks could homogenize medical treatments in patients with severe IBD.
W1283 Infliximab Monotherapy vs. Combined Infliximab-Immunomodulator Therapy in Ulcerative Colitis Yelena Zadvornova, Ashwin N. Ananthakrishnan, Daniel J. Stein, Susan Skaros, Kathryn Johnson, Amar S. Naik, Lilani P. Perera, Mazen Issa Introduction:Combined immunomodulator (IMM) and biologic therapy is superior to IMM or biologic therapy (Infliximab, IFX) alone in IMM naïve Crohn's disease (CD) patients (SONIC trial). The potential benefit of combination therapy in patients with Ulcerative Colitis (UC) has not been adequately defined. The aim of our study was to examine whether the outcomes of UC patients initiated on IFX differed by use of combination therapy. Methods: This single center retrospective study included all UC outpatients initiated on IFX maintenance therapy after the 0, 2,and 6 week induction dosing. Information on demographics, disease extent, age of diagnosis and duration of disease, smoking status, and type of medical therapy was obtained from our database. Combined IMM therapy included azathioprine (AZA), 6-mercaptopurine (6-MP) or methotrexate (MTX). Our primary outcome was occurrence of IFX discontinuation and/or colectomy. For patients able to continue maintenance therapy, duration of IFX treatment was calculated. Cox proportional hazards model was used to identify if combined IMM therapy influenced occurrence of our primary outcome. Results: A total of 104 UC patients were included in our study; 59 patients (57%) were on combination IMM therapy while 44 patients (43%) were on IFX alone. There was no difference in disease duration at IFX initiation (66 months vs. 74 months, p=0.63), sex or extent of disease between the two groups. The proportion of patients with treatment interruption (10% vs. 7%) was also similar between the two groups. The primary outcome occurred in 18 patients in the combined IMM (31%) and 18 patients in the IFX alone group (40%, p=0.31). Ten patients (17%) in the combined IMM and 8 patients (18%) in the IFX alone group underwent colectomy (p=0.91). On multivariate analysis, combined IMM therapy was not predictive of IFX discontinuation or colectomy (Hazard ratio (HR) 1.22, 95% CI 0.54-2.76). Subgroup analysis by IMM type (AZA/6-MP vs. MTX) showed similar outcomes in both groups. Reasons for IFX discontinuation differed between the two groups. Discontinuation due to infusion reaction or drug intolerance was seen in 18% of patients treated with IFX alone compared to only 3% in the combined IMM group (p=0.014). Conclusion: Combination IMM therapy did not influence drug discontinuation or colectomy in UC patients treated with IFX in our single center cohort. Combination therapy was associated with significantly lower likelihood of drug discontinuation due to intolerance or infusion reactions.
W1281 The Phase I Safety and Feasibility Results of Autologous Intravenous Mesenchymal Stromal Cell Treatment in Refractory Crohn's Disease Marjolijn Duijvestein, Manon E. Wildenberg, Barbara B. Wendrich, Anne Christine W. Vos, Auke Verhaar, Herma H. Fidder, Helene Roelofs, Jaap Jan Zwaginga, Willem E. Fibbe, Gijs R. van den Brink, Daniel W. Hommes BACKGROUND Mesenchymal Stromal Cell (MSC) transplantation is being explored as therapy for various indications, including graft versus host disease, myocardial infarction and Crohn's Disease (CD). AIM The aim of this study was to determine the safety and feasibility of autologous bone marrow derived MSC therapy in patients with refractory CD. METHODS Nine adult patients (7 females/2 males) with a median baseline CD activity index (CDAI) score of 317 (224-378) underwent bone marrow aspiration under local anesthesia. Mononuclear cells were isolated and MSCs were expanded and tested for phenotype and functionality In Vitro. Patients received 2 doses of 1-2x10^6 cells/kg bodyweight, intravenously, 7 days apart. Primary outcomes were feasibility and safety of autologous MSC expansion and infusion. Effects on CDAI were recorded as secondary outcome. RESULTS MSC isolated from CD patients showed similar morphology, phenotype and growth potential as those of healthy donors. Moreover, similar differentiation along the adipogenic and osteogenic lineages and In Vitro immunomodulatory capacity was observed, as both healthy donor and CD MSC reduced lymphocyte proliferation up to 70%. MSC infusion was successful and without side effects, besides a mild allergic reaction probably due to the cryopreservant DMSO in one patient. The first patient was a chronic severe steroid refractory patient on the waiting list for surgery. Despite an initial drop in CDAI, she was operated upon due to poor general condition and persistent rectal blood loss before primary endpoint was met. The other patients showed a decrease in median CDAI of 59 points 6 weeks post transplant. Endoscopic improvement was seen in two patients with extensive CD localized in the colon whereas no significant improvement was seen in two patients with ileal CD. CONCLUSIONS Administration of autologous bone marrow derived MSCs appears safe and feasible in the treatment of refractory CD, no serious adverse events were detected during harvesting and study follow up. In addition, possible clinical and endoscopic efficacy was observed.
W1284 The Manitoba IBD Cohort Study: Longitudinal use of Complementary and Alternative Medicine (CAM) in IBD Over 54 Months Patricia Rawsthorne, Kylie I. Bernstein, Rachel Carr, Lesley A. Graff, John R. Walker, Norine Miller, Linda Rogala, Charles N. Bernstein There has been increased and widespread use of CAM in general and for IBD. We aimed to determine the prevalence of CAM use over time in a population-based cohort of IBD patients. Methods: The Manitoba IBD Cohort Study is a longitudinal, population-based study of multiple determinants of health outcomes in those diagnosed with IBD within 7 years at enrolment (mean disease duration=4 years). Participants completed semi-annual selfadministered questionnaires, and participated in annual in-person interviews starting at month 0 to month 54. The questionnaires inquired about use of 13 CAM service providers and 10 CAM products in months 0, 12, 30 and 54; and whether the CAM use was in relation to their IBD in months 12, 30 and 54. Additional services or products were captured under the “Other” category. Results: Approximately 40% of subjects used CAM over the 54 months. Females (n=226) consistently used more CAM than males (n=153) after month 0 (p<0.004). There was no significant difference between subjects with Crohn's (n=186) vs UC (n=193) in use. The most often used services (on average) were massage therapy (21%), chiropractor (10%) and Naturopath/Homeopath/Herbalist (4%). The most often used CAM products were Lactobacillus/acidophilus (6%), fish oils (3%), chamomile (2.7%) and glucosamine (2.5%). 45 subjects used any form of CAM in each time point (14%). 75 subjects (23%) never used any form of CAM in any time point. Conclusions: IBD subjects try CAM quite commonly (77% at some time) although only 14% remain consistent users over a period of 4.5 years. Nearly 40% of users use it for their IBD so the majority use it for other issues. Since its use is so common clinicians need to make a bigger effort in understanding why subjects choose it, where they feel it benefits them and consider whether there are adverse interactions with the management they are prescribing. CAM use over time (all data are in %)
W1282 Infliximab Modulates Mucosal Cytokine Profile in Patients With Inflammatory Bowel Diseases Flavio Caprioli, Francesca Bosè, Lorenzo Raeli, Chiara Viganò, Guido Basilisco, Dario Conte, Sergio Abrignani, Eva Reali Background and aims. Monoclonal antibodies against tumor necrosis factor-alpha (TNFα) are highly effective in the treatment of patients with inflammatory bowel diseases (IBD), even if their mechanism of action has yet to be fully elucidated. In patients with psoriasis, TNFα neutralization has been associated with a reduced dermal expression of proinflammatory cytokines produced by Th1 and Th17 lymphocytes, T cell lineages critically involved also in the pathogenesis of IBD. In this study, we aimed to evaluate the effect of TNFα neutralization by infliximab in modulating mucosal cytokine profile in patients with IBD. Patients and methods. Twelve patients with active left-sided colonic IBD (6 patients with Crohn's disease (CD) and 6 with ulcerative colitis, 7M, median age 34 yrs, range 25-50), and naïve to anti-TNF therapy were enrolled in the study. All patients underwent induction therapy with infliximab (5 mg/kg, administered at week 0, 2 and 6). At enrolment and at week 6 a sigmoidoscopy was performed, and mucosal samples were obtained from the
AGA Abstracts
S-690