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Efficacy of Infliximab Rescue Therapy in Patients With Chronic Refractory Pouchitis: A Multicenter Study
the efficacy of intensification regimes of infliximab and adalimumab in patients with IBD with regard to therapeutic response and ability to return to normal dosing. Methods: All patients with IBD treated in our centre with infliximab or adalimumab between October 2007 and September 2010 were retrospectively reviewed for intensification of therapeutic regimes of biological therapy. Data on start and type of the intervention, response to intervention, ability to return to standard dosing regimen and other details on biological therapy were retrieved from patients' medical files. Results: Totally, 341 courses of infliximab therapy and 111 courses of adalimumab therapy were administered during the study period. Intensification was performed during 47 (14%) infliximab courses (25 in patients with Crohn's disease, 21 with ulcerative colitis and 1 patient with indeterminate colitis) and 14 (13%) adalimumab courses (12 in patients with Crohn's disease and 2 with ulcerative colitis). In infliximab, interval shortening was performed in 33 (70%) cases, dose increase in 6 (13%) and both types of intervention in 8 (17%) treatment courses. In adalimumab therapy only interval shortening to every week was used. The median time to intervention since biological therapy start was 6 months (range 3-21) in infliximab and 3 months (1-7) in adalimumab treatment. The median follow-up after intensification start was 16 months (146). In infliximab group, interval shortening led to clinical response in 22/33 (67%) courses, dose increase in 2/6 (33%) courses and in both interventions response was observed in 4/ 8 (50%) cases. In adalimumab, shortening of interval was effective in 5/14 (36%) cases. Return to normal dosing was possible in half of infliximab courses responding to shortening of interval and combined intervention and in both cases with dose increase. In adalimumab group, 40% of courses obtaining clinical response returned to normal dosing every other week. Conclusions: Intensification of biological therapy restored clinical response in 54% of therapeutic interventions, with shortening of interval in infliximab treatment being the most effective. Approximately in half of the cases the normal dosing regime was possible to restore.
Infliximab Modulates Il23-TH17 Axis in Patients With Inflammatory Bowel Diseases Flavio Caprioli, Francesca Bosè, Chiara Vigano', Marco Palazzo, Guido Basilisco, Dario Conte, Sergio Abrignani, Eva Reali Background and aims. Antibodies against tumor necrosis factor (TNF) represent an effective therapy for patients with inflammatory bowel diseases (IBD), even if their mechanism of action is not fully understood. In patients with psoriasis, TNF neutralization leads to a reduced dermal infiltration by mature dendritic cells and macrophages, and to a reduced expression of Th17-related cytokines. This study was aimed to evaluate the effects of infliximab on intestinal cytokine expression in patients with active IBD, and to correlate the variations with endoscopic response to therapy. Material and methods. 16 patients with active colonic IBD (9 patients with Crohn's disease, CD and 7 patients with ulcerative colitis, UC) and 16 patients with macroscopically normal colon were enrolled in the study. Patients received infliximab therapy at 0, 2 and 6 weeks. At enrollment and at week 6 patients underwent unprepared flexible sigmoidoscopy, and biopsies were taken in the sigmoid colon. Endoscopic disease activity was evaluated through simplified endoscopic score for Crohn's disease (SES-CD) and by Mayo endoscopic subscore, for CD and UC, respectively. Mucosal healing was defined as the disappearance of all ulcers. Mucosal expression of 96 inflammation-related genes was evaluated by qPCR (TaqMan Low Density Array Human Immune Panel, Applied Biosystems) and gene expression data were confirmed by immunofluorescence. Results. At baseline, 40 out of 96 genes were found to be significantly upregulated in the colonic mucosa of patients with active IBD with respect to controls; among them, the expression of 21 genes normalized after 6 weeks therapy with infliximab. We found that variations in gene expression of IL17A (Spearman's rho -0.627, p=0.016), IL8 (Spearman's rho -0.533, p=0.05), p40 (Spearman's rho -0.589, p=0.027), p19 (Spearman's rho -0.531, p= 0.05) and NOS2A (Spearman's rho -0.542, p=0.045) were significantly correlated with endoscopic response to infliximab therapy and with mucosal healing. At immunofluorescence, we confirmed that infliximab therapy induced a reduction in mucosal expression of IL17A in patients achieving mucosal healing, which was associated with a reduced intestinal macrophage infiltration and p19 expression, but not with a reduced lymphocytic infiltrate of the colonic mucosa. Conclusions. We demonstrate that therapy with infliximab induces a modulation in gene expression of both IL23 subunits and IL17A. These results provide further evidences on the mechanism by which this drug modulates intestinal inflammation.
Mo1240 Clinical Experience of Natalizumab in Crohn's Disease Patients at a Tertiary Medical Center Gowri Kularatna, Raja M. Khan, Christian D. Stone, Alexandra Gutierrez, Themistocles Dassopoulos, Chien-Huan Chen Background: Natalizumab (Tysabri) is a humanized monoclonal antibody against a4-integrin that blocks leukocyte migration from the blood vessels to sites of inflammation by inhibiting the action of cell adhesion molecules. The drug was withdrawn from the market in 2005 due to concerns for the risk of progressive multifocal leukoencephalopathy (PML), but was reapproved in 2008 under a restricted distribution program for Crohn's disease (CD) as a second line agent. Since then, there have been limited reports on the effectiveness of natalizumab for CD. Objectives: To evaluate the clinical experience of natalizumab for Crohn's disease at a tertiary medical center in the U.S. Method: A retrospective chart review of all 20 patients who received any number of doses of natalizumab for treatment of refractory CD from January 2008 to August 2010. Results: The mean age of patients was 34.4 yrs. (range 18-53). Sixty percent were female, 75% were white and 25% were black. The median duration of CD at the time of initiation of natalizumab was 14.4 yrs. The location of disease was ileal or small bowel (35%), ileocolonic (35%) and colonic (30%). No actively draining fistulas were present at initiation of natalizumab. Fifteen patients (75%) had undergone at least 1 prior surgical intervention. All patients had received at minimum one prior antiTNF α therapy with discontinuation due to loss of response in the majority of cases. A total of 7 patients (35%) achieved clinical response defined as global improvement of symptoms at the discretion of the treating physicians and have continued natalizumab to date (mean duration 15.4 mo.). No association was seen between clinical response and disease location, duration of disease or smoking status. In 4 patients, natalizumab was stopped prior to completion of induction because it was deemed ineffective. Of the remaining 9 patients who completed induction therapy, 1 had no response, 4 had partial response, 1 lost response and subsequently required colectomy, 1 patient with short gut experienced line infection and sepsis after each dose during induction, 1 did not tolerate the drug due to malaise and lethargy, and 1 had loss of response and headache though unclear if related to natalizumab. One patient had an unintended pregnancy, continued treatment and was induced at 37 weeks due to preeclampsia. The infant suffered from transfusion-requiring anemia and thrombocytopenia, seizures and pneumonia. However, all issues resolved within a month. Other than the adverse events mentioned above, natalizumab was well tolerated. Conclusion: Natalizumab appears to be a safe therapeutic option for refractory CD. In our clinical experience, its effectiveness is similar to previously published trials.
Mo1238 Efficacy of Infliximab Rescue Therapy in Patients With Chronic Refractory Pouchitis: A Multicenter Study Manuel Barreiro-de Acosta, Raquel Souto, Orlando García-Bosch, Míriam Mañosa, Jose Miranda, Valle García-Sánchez, Jordi Gordillo, Silvia Chacon, Daniel Carpio, Nuria Maroto, Luis A. Menchen, Maria Rojas-Feria, Mónica Sierra, Albert Villoria, Ignacio Marin-Jimenez Background: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery during the course of their disease. More than 25% of patients with proctocolectomy with ileal pouch-anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report the efficacy of IFX in these patients and evaluate potential predictors of response. Methods: A retrospective, open-label, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Patients with histology suggestive of Crohn's disease after review of the colectomy specimen were excluded. Short and long term efficacy of IFX was evaluated at weeks 8, 26 and 52, respectively. Remission was defined as cessation of diarrhoea, urgency and blood loss and response as a marked clinical improvement, but persisting symptoms. The pouchitis disease activity index (PDAI) was calculated when available. The influence of gender, tobacco, extraintestinal manifestations, type of surgery and concomitant immunosuppressives on the efficacy of IFX therapy was analyzed. Results are shown as percentages, and were analyzed by the chi-square test and the Fisher exact test, as appropriate. Results: Thirty-one consecutive UC patients with chronic refractory pouchitis were included (16 male, mean age 46, range 21-67), 13% percent were active smokers, 38% had extraintestinal manifestations and 52% received concomitant immunosuppressives. Refractory pouchitis developed after a mean of 49 months. Prior to IFX, 87% of patients had been treated with antibiotics, 28% with probiotics and 61% with immunosuppressive agents. After 8 weeks, 16% of patients with refractory pouchitis achieved remission and 64% showed clinical response. At week 8, 70% of patients had a significant decrease in PDAI score. At week 26, 26% achieved remission and 32% showed clinical response and at week 52, 26% achieved remission and 29% clinical response. Twelve patients (39%) withdrew treatment (4 because of lack of efficacy, 3 because loss of response and 5 for adverse events). Only male gender was associated with a better short-term response (p<0.05), none of the other factors analyzed had influence in response to IFX. Conclusions: IFX was effective in short and long-term in patients with chronic refractory pouchitis. However a high number of patients had to discontinue IFX. More studies are needed in order to evaluate the efficacy of IFX in the treatment of refractory pouchitis.
Mo1241 Outcomes of Treatment With Infliximab for Ulcerative Colitis and Predictors of Sustained Clinical Response Martin Bortlik, Dana Duricova, Karin Malickova, Nadezda Machkova, Viktor Komarek, Eva Bouzkova, Milan Lukas Background & Aim: The purpose of this study was to assess short- and long-term outcomes of infliximab therapy in patients with ulcerative colitis (UC) and to identify potential predictors of sustained clinical response. Methods: This was a retrospective, single center study on all UC patients treated with infliximab between October 2007 and September 2010. Short-term (at week 10) and long-term clinical efficacy including colectomy-free survival were evaluated. Sustained response was defined as the absence of treatment failure due to loss of response or drug intolerance and no need for new introduction of immunomodulators, corticosteroids or their dose increase during infliximab therapy. The impact of disease duration, concomitant immunosuppressive therapy, and short-term endoscopic response at week 10 on sustained response were assessed. Kaplan-Meier curves with log rank test were used for statistical analysis. Results: We enrolled 90 patients with UC (54% females, median age 32 years, (range 10-71)) who obtained 96 courses of IFX therapy. Over a median followup of 21 months (range 0-55) a median number of 8 (range 1-21) infusions were administered. Two thirds of patients had extensive colitis, 31% had left-sided disease, and 3% of patients had proctitis. Eighty four percent of patients responded at week 10, while sustained response was observed in 55% of cases. At the end of follow-up only 13% of patients underwent
Mo1239 Efficacy of Intensification Regimes of Biologic Therapy in Patients With Inflammatory Bowel Disease and Secondary Non-Response: Experience of a Single Referral Centre Milan Lukas, Dana Duricova, Martin Bortlik, Nadezda Machkova, Viktor Komarek, Eva Bouzkova Background: In patients with inflammatory bowel disease (IBD) secondary loss of response to infliximab or adalimumab has been reported between 11% and 48% and constitutes a significant problem in daily clinical practice. Therapy intensification with interval shortening and/or dose increase has been recommended to regain clinical response. Aim: To evaluate
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AGA Abstracts
AGA Abstracts
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Infliximab Modulates Il23-TH17 Axis in Patients With Inflammatory Bowel Diseases Flavio Caprioli, Francesca Bosè, Chiara Vigano', Marco Palazzo, Guido Basilisco, Dario Conte, Sergio Abrignani, Eva Reali Background and aims. Antibodies against tumor necrosis factor (TNF) represent an effective therapy for patients with inflammatory bowel diseases (IBD), even if their mechanism of action is not fully understood. In patients with psoriasis, TNF neutralization leads to a reduced dermal infiltration by mature dendritic cells and macrophages, and to a reduced expression of Th17-related cytokines. This study was aimed to evaluate the effects of infliximab on intestinal cytokine expression in patients with active IBD, and to correlate the variations with endoscopic response to therapy. Material and methods. 16 patients with active colonic IBD (9 patients with Crohn's disease, CD and 7 patients with ulcerative colitis, UC) and 16 patients with macroscopically normal colon were enrolled in the study. Patients received infliximab therapy at 0, 2 and 6 weeks. At enrollment and at week 6 patients underwent unprepared flexible sigmoidoscopy, and biopsies were taken in the sigmoid colon. Endoscopic disease activity was evaluated through simplified endoscopic score for Crohn's disease (SES-CD) and by Mayo endoscopic subscore, for CD and UC, respectively. Mucosal healing was defined as the disappearance of all ulcers. Mucosal expression of 96 inflammation-related genes was evaluated by qPCR (TaqMan Low Density Array Human Immune Panel, Applied Biosystems) and gene expression data were confirmed by immunofluorescence. Results. At baseline, 40 out of 96 genes were found to be significantly upregulated in the colonic mucosa of patients with active IBD with respect to controls; among them, the expression of 21 genes normalized after 6 weeks therapy with infliximab. We found that variations in gene expression of IL17A (Spearman's rho -0.627, p=0.016), IL8 (Spearman's rho -0.533, p=0.05), p40 (Spearman's rho -0.589, p=0.027), p19 (Spearman's rho -0.531, p= 0.05) and NOS2A (Spearman's rho -0.542, p=0.045) were significantly correlated with endoscopic response to infliximab therapy and with mucosal healing. At immunofluorescence, we confirmed that infliximab therapy induced a reduction in mucosal expression of IL17A in patients achieving mucosal healing, which was associated with a reduced intestinal macrophage infiltration and p19 expression, but not with a reduced lymphocytic infiltrate of the colonic mucosa. Conclusions. We demonstrate that therapy with infliximab induces a modulation in gene expression of both IL23 subunits and IL17A. These results provide further evidences on the mechanism by which this drug modulates intestinal inflammation.
Mo1240 Clinical Experience of Natalizumab in Crohn's Disease Patients at a Tertiary Medical Center Gowri Kularatna, Raja M. Khan, Christian D. Stone, Alexandra Gutierrez, Themistocles Dassopoulos, Chien-Huan Chen Background: Natalizumab (Tysabri) is a humanized monoclonal antibody against a4-integrin that blocks leukocyte migration from the blood vessels to sites of inflammation by inhibiting the action of cell adhesion molecules. The drug was withdrawn from the market in 2005 due to concerns for the risk of progressive multifocal leukoencephalopathy (PML), but was reapproved in 2008 under a restricted distribution program for Crohn's disease (CD) as a second line agent. Since then, there have been limited reports on the effectiveness of natalizumab for CD. Objectives: To evaluate the clinical experience of natalizumab for Crohn's disease at a tertiary medical center in the U.S. Method: A retrospective chart review of all 20 patients who received any number of doses of natalizumab for treatment of refractory CD from January 2008 to August 2010. Results: The mean age of patients was 34.4 yrs. (range 18-53). Sixty percent were female, 75% were white and 25% were black. The median duration of CD at the time of initiation of natalizumab was 14.4 yrs. The location of disease was ileal or small bowel (35%), ileocolonic (35%) and colonic (30%). No actively draining fistulas were present at initiation of natalizumab. Fifteen patients (75%) had undergone at least 1 prior surgical intervention. All patients had received at minimum one prior antiTNF α therapy with discontinuation due to loss of response in the majority of cases. A total of 7 patients (35%) achieved clinical response defined as global improvement of symptoms at the discretion of the treating physicians and have continued natalizumab to date (mean duration 15.4 mo.). No association was seen between clinical response and disease location, duration of disease or smoking status. In 4 patients, natalizumab was stopped prior to completion of induction because it was deemed ineffective. Of the remaining 9 patients who completed induction therapy, 1 had no response, 4 had partial response, 1 lost response and subsequently required colectomy, 1 patient with short gut experienced line infection and sepsis after each dose during induction, 1 did not tolerate the drug due to malaise and lethargy, and 1 had loss of response and headache though unclear if related to natalizumab. One patient had an unintended pregnancy, continued treatment and was induced at 37 weeks due to preeclampsia. The infant suffered from transfusion-requiring anemia and thrombocytopenia, seizures and pneumonia. However, all issues resolved within a month. Other than the adverse events mentioned above, natalizumab was well tolerated. Conclusion: Natalizumab appears to be a safe therapeutic option for refractory CD. In our clinical experience, its effectiveness is similar to previously published trials.
Mo1238 Efficacy of Infliximab Rescue Therapy in Patients With Chronic Refractory Pouchitis: A Multicenter Study Manuel Barreiro-de Acosta, Raquel Souto, Orlando García-Bosch, Míriam Mañosa, Jose Miranda, Valle García-Sánchez, Jordi Gordillo, Silvia Chacon, Daniel Carpio, Nuria Maroto, Luis A. Menchen, Maria Rojas-Feria, Mónica Sierra, Albert Villoria, Ignacio Marin-Jimenez Background: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery during the course of their disease. More than 25% of patients with proctocolectomy with ileal pouch-anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report the efficacy of IFX in these patients and evaluate potential predictors of response. Methods: A retrospective, open-label, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Patients with histology suggestive of Crohn's disease after review of the colectomy specimen were excluded. Short and long term efficacy of IFX was evaluated at weeks 8, 26 and 52, respectively. Remission was defined as cessation of diarrhoea, urgency and blood loss and response as a marked clinical improvement, but persisting symptoms. The pouchitis disease activity index (PDAI) was calculated when available. The influence of gender, tobacco, extraintestinal manifestations, type of surgery and concomitant immunosuppressives on the efficacy of IFX therapy was analyzed. Results are shown as percentages, and were analyzed by the chi-square test and the Fisher exact test, as appropriate. Results: Thirty-one consecutive UC patients with chronic refractory pouchitis were included (16 male, mean age 46, range 21-67), 13% percent were active smokers, 38% had extraintestinal manifestations and 52% received concomitant immunosuppressives. Refractory pouchitis developed after a mean of 49 months. Prior to IFX, 87% of patients had been treated with antibiotics, 28% with probiotics and 61% with immunosuppressive agents. After 8 weeks, 16% of patients with refractory pouchitis achieved remission and 64% showed clinical response. At week 8, 70% of patients had a significant decrease in PDAI score. At week 26, 26% achieved remission and 32% showed clinical response and at week 52, 26% achieved remission and 29% clinical response. Twelve patients (39%) withdrew treatment (4 because of lack of efficacy, 3 because loss of response and 5 for adverse events). Only male gender was associated with a better short-term response (p<0.05), none of the other factors analyzed had influence in response to IFX. Conclusions: IFX was effective in short and long-term in patients with chronic refractory pouchitis. However a high number of patients had to discontinue IFX. More studies are needed in order to evaluate the efficacy of IFX in the treatment of refractory pouchitis.
Mo1241 Outcomes of Treatment With Infliximab for Ulcerative Colitis and Predictors of Sustained Clinical Response Martin Bortlik, Dana Duricova, Karin Malickova, Nadezda Machkova, Viktor Komarek, Eva Bouzkova, Milan Lukas Background & Aim: The purpose of this study was to assess short- and long-term outcomes of infliximab therapy in patients with ulcerative colitis (UC) and to identify potential predictors of sustained clinical response. Methods: This was a retrospective, single center study on all UC patients treated with infliximab between October 2007 and September 2010. Short-term (at week 10) and long-term clinical efficacy including colectomy-free survival were evaluated. Sustained response was defined as the absence of treatment failure due to loss of response or drug intolerance and no need for new introduction of immunomodulators, corticosteroids or their dose increase during infliximab therapy. The impact of disease duration, concomitant immunosuppressive therapy, and short-term endoscopic response at week 10 on sustained response were assessed. Kaplan-Meier curves with log rank test were used for statistical analysis. Results: We enrolled 90 patients with UC (54% females, median age 32 years, (range 10-71)) who obtained 96 courses of IFX therapy. Over a median followup of 21 months (range 0-55) a median number of 8 (range 1-21) infusions were administered. Two thirds of patients had extensive colitis, 31% had left-sided disease, and 3% of patients had proctitis. Eighty four percent of patients responded at week 10, while sustained response was observed in 55% of cases. At the end of follow-up only 13% of patients underwent
Mo1239 Efficacy of Intensification Regimes of Biologic Therapy in Patients With Inflammatory Bowel Disease and Secondary Non-Response: Experience of a Single Referral Centre Milan Lukas, Dana Duricova, Martin Bortlik, Nadezda Machkova, Viktor Komarek, Eva Bouzkova Background: In patients with inflammatory bowel disease (IBD) secondary loss of response to infliximab or adalimumab has been reported between 11% and 48% and constitutes a significant problem in daily clinical practice. Therapy intensification with interval shortening and/or dose increase has been recommended to regain clinical response. Aim: To evaluate
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AGA Abstracts
AGA Abstracts
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