- Email: [email protected]
P022 RE-INDUCTION WITH CERTOLIZUMAB PEGOL FOLLOWING DISEASE EXACERBATION DURING MAINTENANCE THERAPY IS EFFECTIVE TO REGAIN RESPONSE AND REMISSION
12
Poster Presentations
P022 RE-INDUCTION WITH CERTOLIZUMAB PEGOL FOLLOWING DISEASE EXACERBATION DURING MAINTENANCE THERAPY IS EFFECTIVE TO REGAIN RESPONSE AND REMISSION G. Lichtenstein 1 , K. Mitchev 2 , G. D' Haens 3 . 1 University of Pennsylvania School of Medicine, Philadelphia, PA, United States; 2 UCB, Braine l' Alleud, Belgium; 3 Imelda General Hospital, Bonheiden, Belgium Background: The efficacy and tolerability of the anti-tumour necrosis factor alpha (TNFα) certolizumab pegol, a PEGylated Fc-free Fab' , in active Crohn' s disease (CD) was demonstrated by the pivotal phase III study, PRECiSE 2.1 At Week 26, response (decrease in CD Activity Index [CDAI] score ≥100 points) rates were 63% with certolizumab pegol and 36% with placebo. Patients who initially responded but then relapsed during maintenance therapy of PRECiSE 2 were entered into the extension study of PRECiSE 4. Objective: To characterise the efficacy of certolizumab pegol in CD for the maintenance of response and remission over 26 weeks, allowing for patients who experience an exacerbation of symptoms to receive re-induction and continued maintenance therapy with certolizumab pegol. Methods: PRECiSE 2 was a multicentre, randomised study of subcutaneous certolizumab pegol 400 mg in patients with moderate-to-severe CD (n=668; CDAI 220-450 points). Following open-label induction at Weeks 0, 2 and 4, Week 6 responders were randomised to maintenance certolizumab pegol 400 mg (n=215) or placebo (n=210) every 4 weeks, from Weeks 8 to 24. Patients with disease exacerbation (CDAI score increase ≥70 points or CDAI score ≥350 points) before Week 26 of PRECiSE 2 could enter PRECiSE 4 and they received three re-induction doses (Weeks 0, 2 and 4) followed by maintenance therapy every 4 weeks. Response was defined by a decrease in HarveyBradshaw Index (HBI) score ≥3 points and remission by an HBI score ≤4 points. An artificial 4-week design was created. Closest visits from PRECiSE 2 and PRECiSE 4 were assigned to these theoretical visits. At withdrawal visit in PRECiSE 4, patients were considered as non-responders. Results: In the certolizumab pegol and placebo groups of PRECiSE 2, 65 and 103 patients, respectively, were withdrawn; 49 and 75 patients had disease exacerbation and entered PRECiSE 4. The mean ± standard deviation time from the last dose in PRECiSE 2 to the first dose in PRECiSE 4 was 24 ± 7 days. In effect, PRECiSE 4 patients differed from PRECiSE 2 patients by only one supplemental injection at Week 2 of PRECiSE 4. Response rates for patients in PRECiSE 2 plus those re-induced in PRECiSE 4 are shown in Table 1. Remission rates at Week 26 were 52.8% in the certolizumab pegol group and 42.4% in the placebo group. Table 1 Visit
Certolizumab pegol induction + Certolizumab pegol induction certolizumab pegol maintenance + placebo maintenance (PRECiSE 2) + re-induction if (PRECiSE 2) + re-induction if necessary (PRECiSE 4) necessary (PRECiSE 4)
Baseline (Week 6), n/N (%) Week 26, n/N (%)
202/215 (94.0)* 154/214 (72.0)
198/208 (95.2)* 116/210 (55.2)
*Week 6 responders were randomised to either placebo or certolizumab pegol.
Conclusions: Re-induction with certolizumab pegol following disease exacerbation during maintenance therapy is an effective therapeutic strategy that results in overall high rates of response and remission in patients with active CD. Reference: 1. Schreiber S et al. N Engl J Med 2007;357:239-250.
P023 INFLIXIMAB DOES NOT INCREASE SHORT-TERM POST-OPERATIVE INFECTIOUS COMPLICATIONS IN PATIENTS WITH ULCERATIVE COLITIS M. Ferrante 1 , S. Vermeire 1 , S. Declerck 1 , A. D' Hoore 2 , G. Van Assche 1 , I. Hoffman 3 , I. Cleynen 1 , I. Arijs 1 , M. Joossens 1, N. Vermeulen 1 , F. Penninckx 2 , P. Rutgeerts 1 . 1 Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium; 2 Department of Abdominal Surgery, University Hospital Leuven, Leuven, Belgium; 3 Department of Paediatric Gastroenterology, University Hospital Leuven, Leuven, Belgium Background & Aim: During the course of their disease, approximately 30% of patients with ulcerative colitis (UC) need to undergo colectomy. Recently, a significant increase in short-term postoperative infectious complications has been reported in patients treated with IFX (1). We determined the impact of IFX on short-term infectious complications in UC patients undergoing proctocolectomy with ileal pouch-anal anastomosis (IPAA) at our referral centre. Methods: A consecutive group of 110 UC patients [43% female, mean (±SD) age 41.8 (± 13.4) years] undergoing IPAA after January 1998 was studied. Short-term postoperative outcomes were compared between 18 patients who received IFX within 6 months prior to IPAA (IFX-group) and 92 patients who did not. Pouch-specific complications included anastomotic leaks and pelvic
abscesses. Infectious complications included pouch-specific complications plus superficial and deep wound infections. Results: At time of pouch construction, there were no significant difference in gender, age, duration of disease, extent of disease, smoking behaviour, body mass index and use of azathioprine/6-mercaptopurine between the IFX-group and IFX-naïve patients. Patients in the IFX-group were less often taking corticosteroids (11 Vs. 58%, p<0.001) and cyclosporine (11 Vs. 33%, p=0.066) prior to IPAA, and the pouch was less often constructed at a first stage surgery (50 Vs. 77%, p=0.018). Median (IQR) C-reactive protein levels at pouch construction where significantly lower in the IFX-group [5.0 (1.2-12.37) Vs. 12.7 (3.6-32.6) mg/L, p=0.041]. The median (IQR) duration between last IFX and IPAA was 3.3 (1.8-4.7) months. The overall shortterm mortality was nil. Although not significant, patients in the IFX-group developed less often pouch-specific (16% Vs. 27%, p=0.554) and infectious complications (17% Vs. 28%, p=0.391). Median post-IPAA hospital stay was not significantly different compared to IFX-naïve patients [11 (9-13) Vs. 12 (10-15) days, p=0.092], and this regardless of the stage of surgery. In multivariate analysis, none of the investigated clinical, therapeutic (IFX, steroids, immunosuppressive agents) and surgical variables was independently associated with pouch-specific or infectious complications. Conclusion: Pre-operative treatment with IFX does not increase short-term post-operative pouch-specific and infectious complications in UC patients undergoing IPAA. Reference: 1. Selvasekar, J Am Coll Surg 2007
P024 D2-40 IN COLONIC BIOPSIES: A USEFUL TOOL IN THE DIFFERENTIAL DIAGNOSIS BETWEEN CROHN' S DISEASE AND ULCERATIVE COLITIS F. Pedica, C. Ligorio, P. Baccarini. Bellaria Hospital, Bologna, Italy Aim: Crohn' s disease (CD) and Ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown etiology. Endoscopic biopsies are often one of the first approaches to the evaluation of a patient with IBD but sometimes morphological features are not clear enough to distinguish between UC and CD. CD can present with a colonic involvement alone and UC may show unusual CD-like features, such as discontinuous or patchy disease, ileal inflammation, extracolonic involvement, granulomatous inflammation or aphthous ulcers. In a previous study [1] we found out that lymphatic microvessels present a different distribution in the lamina propria (LP) of UC colonic samples compared to CD. The aim of this study was to evaluate if the different distribution of lymphatics in endoscopic mucosal biopsies of patients with IBD can help in making a correct histological diagnosis, especially in problematic cases. Materials and methods: We investigated a series of colonic biopsies taken from 29 patients with well-established UC (14 cases) and CD (15 cases). All patients were affected by active disease. Ten samples of normal colon were taken as comparison. Immunohistochemical staining was performed using the monoclonal antibody D2-40 (Signet), a highly specific marker for lymphatic vessels, on paraffin-embedded sections. Results: We evaluated the presence and localization of lymphatic microvessels within the LP of all samples. In normal colonic mucosa, lymph vessels were located immediately superficial to the muscolaris mucosae while they were lacking in the upper LP, as previously described [2]. In the LP of colonic biopsies of CD patients, lymphatics were rare or absent, despite the presence of marked inflammatory changes. Rare and small lymph vessels were exclusively present close to mucosal ulceration. On the contrary, in all cases of UC, the LP was characterized by a remarkable quantity of lymphatic microvessels, often with visible lumen, reaching the upper part of LP, near the surface epithelium. Conclusions: CD and UC are the two most common forms of IBD. Since there are no specific clinical or laboratory features, the diagnosis relies heavily on pathological interpretation of endoscopic biopsies. Unfortunately, CD and UC can show overlapping pathological features so that definite distinction between these two disorders is sometimes difficult. In this study we demonstrated relevant differences in the distribution of lymphatic vessels in the LP of colonic mucosal biopsies of CD patients compared to UC. We suggest that D2-40 antibody may be a useful tool in distinguishing between these two entities and therefore to achieve a correct diagnosis for a proper treatment of the patient. References: 1. Pedica F et al. “Lymphangiogenesis in Crohn' s disease: an immunohistochemical study using monoclonal antibody D2-40” Virchows Archiv 2008 (in press); 2. Fenoglio CM et al. “Distribution of human colonic lymphatics in normal, hyperplastic, and adenomatous tissue. Its relationship to metastasis from small carcinomas in pedunculated adenomas, with two case reports” Gastroenterology 1973; 64: 51-66
Poster Presentations
P022 RE-INDUCTION WITH CERTOLIZUMAB PEGOL FOLLOWING DISEASE EXACERBATION DURING MAINTENANCE THERAPY IS EFFECTIVE TO REGAIN RESPONSE AND REMISSION G. Lichtenstein 1 , K. Mitchev 2 , G. D' Haens 3 . 1 University of Pennsylvania School of Medicine, Philadelphia, PA, United States; 2 UCB, Braine l' Alleud, Belgium; 3 Imelda General Hospital, Bonheiden, Belgium Background: The efficacy and tolerability of the anti-tumour necrosis factor alpha (TNFα) certolizumab pegol, a PEGylated Fc-free Fab' , in active Crohn' s disease (CD) was demonstrated by the pivotal phase III study, PRECiSE 2.1 At Week 26, response (decrease in CD Activity Index [CDAI] score ≥100 points) rates were 63% with certolizumab pegol and 36% with placebo. Patients who initially responded but then relapsed during maintenance therapy of PRECiSE 2 were entered into the extension study of PRECiSE 4. Objective: To characterise the efficacy of certolizumab pegol in CD for the maintenance of response and remission over 26 weeks, allowing for patients who experience an exacerbation of symptoms to receive re-induction and continued maintenance therapy with certolizumab pegol. Methods: PRECiSE 2 was a multicentre, randomised study of subcutaneous certolizumab pegol 400 mg in patients with moderate-to-severe CD (n=668; CDAI 220-450 points). Following open-label induction at Weeks 0, 2 and 4, Week 6 responders were randomised to maintenance certolizumab pegol 400 mg (n=215) or placebo (n=210) every 4 weeks, from Weeks 8 to 24. Patients with disease exacerbation (CDAI score increase ≥70 points or CDAI score ≥350 points) before Week 26 of PRECiSE 2 could enter PRECiSE 4 and they received three re-induction doses (Weeks 0, 2 and 4) followed by maintenance therapy every 4 weeks. Response was defined by a decrease in HarveyBradshaw Index (HBI) score ≥3 points and remission by an HBI score ≤4 points. An artificial 4-week design was created. Closest visits from PRECiSE 2 and PRECiSE 4 were assigned to these theoretical visits. At withdrawal visit in PRECiSE 4, patients were considered as non-responders. Results: In the certolizumab pegol and placebo groups of PRECiSE 2, 65 and 103 patients, respectively, were withdrawn; 49 and 75 patients had disease exacerbation and entered PRECiSE 4. The mean ± standard deviation time from the last dose in PRECiSE 2 to the first dose in PRECiSE 4 was 24 ± 7 days. In effect, PRECiSE 4 patients differed from PRECiSE 2 patients by only one supplemental injection at Week 2 of PRECiSE 4. Response rates for patients in PRECiSE 2 plus those re-induced in PRECiSE 4 are shown in Table 1. Remission rates at Week 26 were 52.8% in the certolizumab pegol group and 42.4% in the placebo group. Table 1 Visit
Certolizumab pegol induction + Certolizumab pegol induction certolizumab pegol maintenance + placebo maintenance (PRECiSE 2) + re-induction if (PRECiSE 2) + re-induction if necessary (PRECiSE 4) necessary (PRECiSE 4)
Baseline (Week 6), n/N (%) Week 26, n/N (%)
202/215 (94.0)* 154/214 (72.0)
198/208 (95.2)* 116/210 (55.2)
*Week 6 responders were randomised to either placebo or certolizumab pegol.
Conclusions: Re-induction with certolizumab pegol following disease exacerbation during maintenance therapy is an effective therapeutic strategy that results in overall high rates of response and remission in patients with active CD. Reference: 1. Schreiber S et al. N Engl J Med 2007;357:239-250.
P023 INFLIXIMAB DOES NOT INCREASE SHORT-TERM POST-OPERATIVE INFECTIOUS COMPLICATIONS IN PATIENTS WITH ULCERATIVE COLITIS M. Ferrante 1 , S. Vermeire 1 , S. Declerck 1 , A. D' Hoore 2 , G. Van Assche 1 , I. Hoffman 3 , I. Cleynen 1 , I. Arijs 1 , M. Joossens 1, N. Vermeulen 1 , F. Penninckx 2 , P. Rutgeerts 1 . 1 Department of Gastroenterology, University Hospital Leuven, Leuven, Belgium; 2 Department of Abdominal Surgery, University Hospital Leuven, Leuven, Belgium; 3 Department of Paediatric Gastroenterology, University Hospital Leuven, Leuven, Belgium Background & Aim: During the course of their disease, approximately 30% of patients with ulcerative colitis (UC) need to undergo colectomy. Recently, a significant increase in short-term postoperative infectious complications has been reported in patients treated with IFX (1). We determined the impact of IFX on short-term infectious complications in UC patients undergoing proctocolectomy with ileal pouch-anal anastomosis (IPAA) at our referral centre. Methods: A consecutive group of 110 UC patients [43% female, mean (±SD) age 41.8 (± 13.4) years] undergoing IPAA after January 1998 was studied. Short-term postoperative outcomes were compared between 18 patients who received IFX within 6 months prior to IPAA (IFX-group) and 92 patients who did not. Pouch-specific complications included anastomotic leaks and pelvic
abscesses. Infectious complications included pouch-specific complications plus superficial and deep wound infections. Results: At time of pouch construction, there were no significant difference in gender, age, duration of disease, extent of disease, smoking behaviour, body mass index and use of azathioprine/6-mercaptopurine between the IFX-group and IFX-naïve patients. Patients in the IFX-group were less often taking corticosteroids (11 Vs. 58%, p<0.001) and cyclosporine (11 Vs. 33%, p=0.066) prior to IPAA, and the pouch was less often constructed at a first stage surgery (50 Vs. 77%, p=0.018). Median (IQR) C-reactive protein levels at pouch construction where significantly lower in the IFX-group [5.0 (1.2-12.37) Vs. 12.7 (3.6-32.6) mg/L, p=0.041]. The median (IQR) duration between last IFX and IPAA was 3.3 (1.8-4.7) months. The overall shortterm mortality was nil. Although not significant, patients in the IFX-group developed less often pouch-specific (16% Vs. 27%, p=0.554) and infectious complications (17% Vs. 28%, p=0.391). Median post-IPAA hospital stay was not significantly different compared to IFX-naïve patients [11 (9-13) Vs. 12 (10-15) days, p=0.092], and this regardless of the stage of surgery. In multivariate analysis, none of the investigated clinical, therapeutic (IFX, steroids, immunosuppressive agents) and surgical variables was independently associated with pouch-specific or infectious complications. Conclusion: Pre-operative treatment with IFX does not increase short-term post-operative pouch-specific and infectious complications in UC patients undergoing IPAA. Reference: 1. Selvasekar, J Am Coll Surg 2007
P024 D2-40 IN COLONIC BIOPSIES: A USEFUL TOOL IN THE DIFFERENTIAL DIAGNOSIS BETWEEN CROHN' S DISEASE AND ULCERATIVE COLITIS F. Pedica, C. Ligorio, P. Baccarini. Bellaria Hospital, Bologna, Italy Aim: Crohn' s disease (CD) and Ulcerative colitis (UC) are inflammatory bowel diseases (IBD) of unknown etiology. Endoscopic biopsies are often one of the first approaches to the evaluation of a patient with IBD but sometimes morphological features are not clear enough to distinguish between UC and CD. CD can present with a colonic involvement alone and UC may show unusual CD-like features, such as discontinuous or patchy disease, ileal inflammation, extracolonic involvement, granulomatous inflammation or aphthous ulcers. In a previous study [1] we found out that lymphatic microvessels present a different distribution in the lamina propria (LP) of UC colonic samples compared to CD. The aim of this study was to evaluate if the different distribution of lymphatics in endoscopic mucosal biopsies of patients with IBD can help in making a correct histological diagnosis, especially in problematic cases. Materials and methods: We investigated a series of colonic biopsies taken from 29 patients with well-established UC (14 cases) and CD (15 cases). All patients were affected by active disease. Ten samples of normal colon were taken as comparison. Immunohistochemical staining was performed using the monoclonal antibody D2-40 (Signet), a highly specific marker for lymphatic vessels, on paraffin-embedded sections. Results: We evaluated the presence and localization of lymphatic microvessels within the LP of all samples. In normal colonic mucosa, lymph vessels were located immediately superficial to the muscolaris mucosae while they were lacking in the upper LP, as previously described [2]. In the LP of colonic biopsies of CD patients, lymphatics were rare or absent, despite the presence of marked inflammatory changes. Rare and small lymph vessels were exclusively present close to mucosal ulceration. On the contrary, in all cases of UC, the LP was characterized by a remarkable quantity of lymphatic microvessels, often with visible lumen, reaching the upper part of LP, near the surface epithelium. Conclusions: CD and UC are the two most common forms of IBD. Since there are no specific clinical or laboratory features, the diagnosis relies heavily on pathological interpretation of endoscopic biopsies. Unfortunately, CD and UC can show overlapping pathological features so that definite distinction between these two disorders is sometimes difficult. In this study we demonstrated relevant differences in the distribution of lymphatic vessels in the LP of colonic mucosal biopsies of CD patients compared to UC. We suggest that D2-40 antibody may be a useful tool in distinguishing between these two entities and therefore to achieve a correct diagnosis for a proper treatment of the patient. References: 1. Pedica F et al. “Lymphangiogenesis in Crohn' s disease: an immunohistochemical study using monoclonal antibody D2-40” Virchows Archiv 2008 (in press); 2. Fenoglio CM et al. “Distribution of human colonic lymphatics in normal, hyperplastic, and adenomatous tissue. Its relationship to metastasis from small carcinomas in pedunculated adenomas, with two case reports” Gastroenterology 1973; 64: 51-66