- Email: [email protected]
Response Evaluation and Safety of Thiopurines in the Treatment of Inflammatory Bowel Diseases (IBD)
AGA Abstracts
2008;20:629). We hypothesized effectiveness of GMA and LMA might be dependent on depletion of granulocyte and monocytes. S100A12 was reported to be exclusively expressed in neutrophils and up-regulated by TNF α. The aim of this study was to investigate the changes of serum S100 A12 concentration in the GMA treatments and whether S100A12 increases the expression of adhesion molecules, CXCL and CCL chemokines. Methods; 24 patients with ulcerative colitis were treated with GMA. Serum S100A12 was estimated by ELISA methods. Clinical activity index (CAI) and serum CRP concentration were also checked. Immunohistochemical staining of S100A12 and receptor for advanced glication end products (RAGE) were performed in the operated specimens of patients with ulcerative colitis and with colonic carcinoma (control). HUVEC were seeded into 12 well plates and confluent plates were used to experiments. Each experiment was performed in triplicate. HUVEC were treated with human recombinant S100A12 protein. RNA was extracted by RNeasy Mini Kit. 1.5μg RNA was reverse-transcriptated into cDNA. ICAM-1, VCAM-1, IL-8, CCL-2 (MCP1), CCL5 (RANTES), CXCL9 (IP-10) and CXCL10 (Mig) mRNA was quantitated by realtime PCR. Results; S100A12 staining was faintly recognized in the mucosal layer of normal control. S100A12 staining was increased in infiltrating cells in inflamed colon in patients with ulcerative colitis. Strong staining was also recognized in crypt abscess. RAGE staining was also faintly recognized in the epithelial cells in nornmal control. However, RAGE staining was increased in the inflamed epithelial cells. Significantly serum S100A12 concentration was positively correlated with CAI (n=34, p=0.02, rs=0.404). 16 patients were able to estimate S100A12 concentration in the points of pre- and post-GMA treatment. 13 patients were GMA-responders and 3 patients were non GMA-responders. Serum S100A12 concentration was significantly decreased in GMA responders (pre- vs post- GMA, 1.34±1.08 vs 0.60±0.50, p<0.05). However, Serum S100A12 concentration of non GMA- responders was gradually increased with GMA treatments. ICAM-1, VCAM-1, IL-8, IP-10, Mig, MCP-1 and RANTES mRNA expressions were increased by S100A12 in HUVEC cell lines in time and dose-dependent manners. Conclusion; one of the mechanisms of GMA effect might be correlated with depletion of S100A12 by adsorption of activated neutrophils. S100A12 might aggravate acute and chronic inflammation by up-regulation of adhesion molecules, CXCL and CCL chemokines.
using MTX with a dosage of at least 15 mg/week at 6, 12, 24 and 60 months after initiation of MTX therapy and were considered to be in clinical remission, based on global physician's assessment, laboratory, radiological and/or endoscopic findings. Reasons for discontinuation of MTX were subclassified into adverse events, ineffectiveness, patient's request, pregnancy wish and others. Results: Seventy-eight CD-patients (57 females) were included. The median duration of IBD at initiating MTX therapy was 4 years (IQR 2-13 years) with a median age of 36 years (IQR 26-45 years). Fourty-eight patients (62%) initiated MTX therapy due to an adverse reaction to thiopurines, 17 patients due ineffectiveness of thiopurines, 3 patients had an adverse reaction to combination therapy of thiopurine and a biological and in 9 patients ineffectiveness of combination therapy. MTX therapy was discontinued in 49 patients (63%) after a median duration of 33 weeks (IQR 12-99 weeks) due to adverse events (35%), ineffectiveness (39%), patient's request (10%), pregnancy wish (8%), others (6%) and 1 unknown. Median duration of MTX use in the 29 patients who continued therapy was 162 weeks (IQR 101-231 weeks). In 8 of these 29 patients a biological agent was added after initiating MTX therapy due to ineffectiveness of monotherapy with MTX. The proportion of patients still using MTX at 6, 12, 24 and 60 months was, 73%, 59%, 44% and 9% respectively. Conclusion: After one year of MTX-therapy, effectiveness was established in 59 percent in CD patients. This percentage decreased to 9% after 5 years, mainly due to ineffectiveness or adverse reactions. Sa1319 To Determine the Relationship Between Time of Anti-TNFα Therapy Initiation and Anti-TNFα Dose Escalation Mindy Ching Wan Lam, Kenneth Atkinson, Brian Bressler BACKGROUND Factors which influence dose escalation for anti-tumor necrosis factor α (anti-TNF α) therapy in Crohn's disease (CD) are largely unknown. Approximately 50% of patients receiving anti-TNF therapy lose response for unclear reasons. Immunogenicity data does not suggest a coorelation to clinical response. The inflammatory burden in patients with CD is most early in the course of disease, and may influence the sustainability of infliximab therapy. AIM To determine if early initiation of anti-TNF α therapy will affect the need for dose escalation. METHOD This was a retrospective cohort study of biologic naïve patients on infliximab for Crohn's disease from 2 outpatient gastroenterology clinics during July 2009 to October 2010. All patients had moderately to severe CD (HBI > 8) Patients were divided into groups based on length of time between diagnosis to therapy initiation and concurrent immunosuppressant therapy. A Cox proportional hazards model was used to compare the time to dose escalation for the various groups. RESULTS Sixty eight patients comprised this cohort 53% males with an average age at diagnosis of 24.4±11.3 years, and average age of infliximab initiation of 33.7±14.8 years. Of the 68 patients, 29% initiated inflixiamb within two years of diagnosis, and 46% had concurrent immunosuppressant therapy at time of therapy initiation. There was a statistically significant lower probability of requiring dose esclataion in patients who initiated biologic therapy after two years but less than 12 years of diagnosis compared to those initiated within two years (p=0.049). Furthermore, the group whom therapy initation occurred within two years and not on immunosuppresant therapy had the highest probability of requiring dose escalation (p= 0.485). CONCLUSION Compared to patients diagnosed with Crohns disease greater than 2 years from initiating infliximab, those who receive infliximab within 2 years of diagnosis require more intense immunosuppressive therapy to avoid dose escalation. Strategies to avoid dose escalation must be studied. As suggested by this study, optimal induction thearpy (combined immunosuppressive therapy) in patients with a significant inflammatory burden is critical.
Sa1317 Fixed Weight Based Thiopurine Dosing Lowers Steroid Free Remission Rates in Crohn's Disease Chadwick I. Williams, Allen Greenwood, Evan Norris, Nadine Mokhallati, Gil Y. Melmed, Dermot P. McGovern, Marla Dubinsky Background: Thiopurine agents are commonly used to manage Crohn's disease (CD). Studies have shown that optimizing drug dosage based on therapeutic drug monitoring maximizes clinical benefit. Fixed weight-based dosing of thiopurine agents is often employed in clinical practice. Thiopurine metabolism, however, varies irrespective of weight. Fixed weight-based dosing can result in sub-optimal clinical outcomes. A previous study found that the 6 month steroid-free remission rate for patients on fixed weight-based thiopurine monotherapy was only 30 %. Titrating drug dose to achieve therapeutic metabolite (6-thioguanine [6-TGN] > 235) levels may improve steroid free remission rates in CD. Aims 1) Determine the frequency of patients achieving 6-TGN > 235 initiating standard weight based doses of thiopurines without dose escalation 2) determine the 6 month steroid free remission rate in patients achieving 6-TGN > 235. Methods: Clinical records of all pediatric CD patients seen at Cedars-Sinai Medical Center from August 2001- July 2010 were reviewed. Patients were eligible for inclusion if they were on standard weight-based doses of thiopurines (at least equivalent to 2.5mg/kg of azathioprine) at baseline. Patients were excluded if they had previous or on-going anti-TNF therapy, missing 6-TGN levels or low or absent thiopurine methyltransferase (TPMT) activity. Clinical data was collected at baseline and then every three months and included Harvey-Bradshaw index, steroid and thiopurine dose and laboratory indices. Thiopurine metabolite levels were routinely obtained 4-8 weeks after initiating standard dosing and again at 6 months. Results: Of the 102 total patients studied, only 24% initiating standard dosing did not undergo dose escalation (Group 1). These patients had a median initial 6TGN level of 288 and their 6-month steroid free remission rate was 42%. The remaining 76% of patients had at least one dose escalation (Group 2) based on a subtherapeutic initial 6TGN level (median=165). The 6-month steroid free remission rate in Group 2 was 51% with a median 6TGN level at 6 months of 313 vs 195 for those not in remission. One third of patients did not achieve remission with a 6-TGN level > 235. The mean dose of thiopurines in the group who underwent dose escalation was 3.4 mg/kg at 6 months. The average dose increase needed to achieve steroid free remission was 1.2 mg/kg. Only 8% of patients failed thiopurines due to drug toxicity. Conclusion: The majority of CD patients initiating standard weight based thiopurines dosing do not achieve therapeutic 6-TGN levels in the absence of dose escalation. This could explain reported suboptimal steroid free remission rates Prior to declaring a patient a thiopurine failure, dosing should be optimized so to maximize clinical benefit prior to switching to another class of therapy.
Sa1320 Sa1318 Response Evaluation and Safety of Thiopurines in the Treatment of Inflammatory Bowel Diseases (IBD) Giuseppe Costantino, Federica Furfaro, Alessandra Belvedere, Gionata Fiorino, Angela Alibrandi, Walter Fries
Effectiveness and Tolerability of Maintenance Methotrexate Therapy in Crohn's Disease Patients; Analysis of a Referral Hospital-Based 10-Years Intercept Cohort Margien L. Seinen, Nanne K. de Boer, Chris J. Mulder, Gerd Bouma, Adriaan A. van Bodegraven
Thiopurines (THIO) are widely used in inflammatory bowel disease (IBD). Besides adverse events (AE), the main drawbacks of THIO therapy are the slow onset of action and the difficulty to predict response to therapy. The aims of our study were to investigate predictors of response, efficacy, and safety of THIO therapy. METHODS: We analyzed the charts of IBD patients treated at our clinic with THIO. Harvey-Bradshaw index (HBI) or partial Mayo score (pMS) before and after 6,12,24 and 36 months of treatment with THIO were registered. Indications for treatment, disease duration, smoking status, and AE were recorded. AE were divided in early (within 4 wks), intermediate (from 2 to 6 months) and late (>6 months). A subgroup of patients with available data on C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), erythrocytes (RBC), mean corpuscular volume (MCV), leucocytes (WBC), neutrophils (NBC) prior to start of THIO and at 6 months was analyzed for predictors of clinical response. RESULTS: We identified 266 patients (157 CD, 109 UC) treated with
Background & Aim: Methotrexate (MTX) is a frequently administered immunomodulating drug for the treatment of Crohn's disease (CD). Unfortunately, limited longterm data are available. The aim of this study is to assess the maintenance effectiveness and tolerability of methotrexate (MTX) as maintenance therapy in Crohn's disease patients. Material and methods: A referral hospital-based, intercept cohort from January 1st, 2000, until January 1st, 2010 was explored to evaluate all consecutive MTX-using CD-patients. In this retrospective study, these patients were selected from a prospectively maintained database concerning all IBD-patients. MTX was initiated in patients after previous immunosuppressive therapies (mostly thiopurine, or combination with anti-TNFα), according to a step-up protocol. Therapeutic effectiveness was assessed by calculating the cumulative number of patients still
AGA Abstracts
S-280
THIO. Indications were steroid dependency, 71%, perianal fistulas, 4.5%, post-surgery recurrence, 8.3%, extensive disease, 13.6%, other, 2.3%. The mean disease duration was 5.3 yrs ± 8.7. The HBI and pMS fell significantly compared to pretreatment values at 6 months up to 3 yrs (all p<0.001 vs pre-treatment). Adverse events (AE) were analyzed on 733 patient-years. Overall 115 AE occurred in 87 patients (32.7%), 14 (16.1%) resolved with dose reduction, 70 patients (80.5%) discontinued THIO because of AE. We observed early AE in 41 patients, the most frequent were flu-like syndrome, 13.5%, nausea, vomiting or abdominal pain, 8.7%, pancreatic hyperenzymemia, 7.8%; intermediate AE in 16, the most frequent was hepatotoxicity (8.7%); late AE in 30, the most frequent were leucopenia, 9.6 %, infections, 7.8%, hepatotoxicity, 5.2%. For response analysis, data were available from 96 Responders (R) and 43 Non-R (NR). Clinical activity fell significantly in R (p<0.001, both CD and UC), but not in NR. Significant (p<0.001) drops were registered for CRP, ESR, WBC, and NBC in R, but only for WBC in NR. In both groups MCV increased significantly (p<0.001, both). Patients with shorter disease duration responded better to therapy (p=0.007). CONCLUSIONS: THIO are equally effective in CD and UC, maintaining efficacy over time. AE did occur in 32.7 % of patients leading to drug discontinuation in 26.3% of patients. Among late occurring AE, leucopenia, liver toxicity, and infections were the most frequent, emphasizing the need for continuous surveillance. CRP, ESR and NBC are useful markers to predict clinical response to thiopurines therapy in IBD patients, whereas the increase of MCV did not distinguish between N and NR. Early use of thiopurines was associated with better response to therapy.
success, whereas significantly shorter symptom-free interval was found in patients on biological therapy.
6-Thioguanine Measurement Allows Optimisation in Management of IBD Patients on Azathioprine Grace E. Dolman, Heather E. Johnson, Simon D. McLaughlin, Begley Joseph, Sean Weaver Introduction: Azathioprine is widely used in the management of Inflammatory Bowel Disease (IBD). The ideal dose for a patient is usually calculated by weight, but the rate of metabolism of azathioprine to its active metabolite 6-thioguanine (6TGN) varies between individuals. In addition, therapy may be limited by non-compliance, side effects or relapse of disease while on treatment. This retrospective study evaluates whether measuring 6TGN levels alters the management of patients on azathioprine for IBD. Methods: A search of laboratory records identified a cohort of 41 patients with IBD that had been tested for 6TGN levels. 48 tests had been performed as 7 patients were tested twice. Electronic and, when required, paper records were reviewed to record demographics and diagnosis. The reason for checking 6TGN level and how this altered management was evaluated. Results: The cohort was mainly young adults, with an age range of 18-73 years (median 36 years), and a slight female predominance (22F:19M). 66% of patients had Crohn's disease, the remainder Ulcerative Colitis (UC). Tests were performed because patients were symptomatic, suspected of non-compliance, had abnormal liver biochemistry or to confirm a therapeutic dose. Of the 48 tests performed, 12 (25%) identified low 6TGN levels. Compliance was addressed in 3 cases. Dose of azathioprine was increased in 6 cases and management was altered in 2 cases. 20 tests (42%) were within the therapeutic range and azathioprine dose was only increased following 3 of these tests. 4 patients required escalation of treatment to alternative medication or surgery. 16 tests (33%) were above the recommended level of 6TGN, despite all the patients receiving <2.7mg/kg of azathioprine and 4 patients receiving less than 2mg/kg. 5 patients with high 6TGN levels were subsequently switched to an alternative agent for maintenance therapy. 29 (60%) of all tests were performed on symptomatic patients to confirm adequate dosing before declaring a treatment failure. By weight calculation, 11 of these patients were receiving subtherapeutic doses of azathioprine. However, contrary to expectation, only 5 of 11 had low levels of 6TGN. Conclusion: Calculation of azathioprine dose by weight does not address individual variation in metabolism to the active component, 6TGN. In this retrospective study, management was altered in 51% of patients as a result of measuring 6TGN, with either alteration of dose, or change of therapy. The cost of the assay (£29/$50 US) limits its use, and currently we would recommend the use of 6TGN as a useful adjunct to established measures for azathioprine dose adjustment, such as clinical response and haematological indices.
Sa1321 Major Role of Sustained Drainage in the Management of Fistulizing Perianal Crohn's Disease Under Anti-TNF Therapy: A Cohort Study of 81 Patients With Successful Long Term Follow-up Audrey Haennig, Benoît Lepage, Ghislain Staumont, Philippe Otal, Jean Michel Suduca, Etienne Gorez, Patrick Faure, Guillaume Bonnaud, Barbara Bournet, Laurent Alric, Louis Buscail, Jean R. Escourrou, Jacques Moreau Perianal fistulas are one of major causes of disability in Crohn's disease. Medical treatment including biological therapies such as infliximab or adalumimab have been tried with varying degrees of success not exceeding roughly 40 to 50%. The aim of our study was to assess the efficacy and the specific role of biotherapy and local surgery on sustained fistula closure and to evaluate good and bad predicting factors in this field. Patients and methods: 81 patients (H: 39; F: 42; mean age: 31 years) with fistulizing perianal Crohn's disease were followed consecutively and prospectively. These patients are issued from a 10 years large regional cohort. Examination under anesthesia was performed in 95% patients. Fistulas were complex in 87% of cases. Luminal Crohn disease was severe (Harvey Bradshaw mean score=6). Median follow-up was 69 months. Anti-TNFα (mainly Infliximab) treatment was administered in 76.5% of patients. Seton drainage was realized in most cases (80.5%). Good response was defined as a complete fistula closure. Clinical and morphological data were subjected to simple and multivariate analysis. Log rank test estimates and Kaplan Meier curves were established with the main confounding factors. Results: Fistula closure was initially observed in 87.7% of cases after a median follow-up of 12.7 months. Setons were maintained for a median duration of 3.8 months. Fistula recurrence was observed in 47% of cases at a median time of 38.5 months (29% at one year). Twenty two reopened fistulas were redrained by using the same procedure for a median time of 4 months. Fistula closure after recurrence occurred in 66.8% of cases at a median time of 48 months. The global rate of healing in our study was then 73%. Multivariate analysis identified as the main poor prognostic factors: female gender, rectovaginal fistula, complex fistula, anal stenosis. Median duration of drainage was associated with good clinical response ahead the duration of biological therapy itself. Conclusion: Among this large cohort, prolonged seton placement and other local surgical procedures combined with infliximab resulted in complete healing in nearly ¾ of patients. These results are dramatically better than those that have been published until now. Whatever the biotherapy modalities, duration of drainage appears to be the best guarantee of long term success.
Sa1324 The Risk Factors of Surgical Recurrence in Patients With Crohn's Disease After First Intestinal Surgery Hyun Jin Jo, Kyu Joo Park, Mi Na Kim, Jong Pil Im, Sang Gyun Kim, Hyun Chae Jung, In Sung Song, Joo Sung Kim Backgrounds/Aims: Although the rate of surgery in patients with Crohn's disease (CD) is up to 80%, the risk factors for surgical recurrence except for smoking and penetrating disease behavior remain undetermined. The aim of this study was to identify clinical factors that influence the risk of surgical recurrence in CD patients. Methods: A total of 97 CD patients underwent first intestinal resection were consecutively enrolled from January 1985 to April 2010, and analyzed retrospectively. These patients were grouped according to the Montreal classification, and then clinical characteristics, medical treatment and type of surgery were analyzed. We obtained cumulative surgical recurrence rate and analyzed clinical predictors of surgical recurrence using Cox proportional hazards regression model. Results: A mean follow-up period after first intestinal resection was 91 (range: 1-449) months. Disease behavior at first operation was classified as penetrating type (51%), stricture type (33%), and non-penetrating/non-stricture type (16%). After first operation, 27 (28%) patients underwent second operation for the recurrence of CD. At second operation, concordance of disease behavior was found in 23 (85%) patients (OR 32.5, p<0.001). The overall cumulative reoperation rates at 1, 5, 10 and 15 years were 8%, 26%, 47% and 64%, respectively. In Cox regression analysis, delayed diagnosis (HR 1.023, 95% CI 1.010-1.035, p<0.001) and occurrence of perianal disease after first intestinal surgery (HR 4.267, 95% CI 1.176-15.483, p=0.027) were associated with increased risk of re-operation while diagnosis at old age (HR 0.942, 95% CI 0.896-0.991, p=0.021) was associated with decreased risk. Conclusions: Delayed diagnosis and perianal disease were risk factors of surgical recurrence in patients with CD.
Sa1322 Endoscopic Balloon Dilatation of Anastomotic Strictures in Patients With Crohn's Disease: Effect of Immediate Endoscopic Success and Biological Therapy Martin Bortlik, Eva Bouzkova, Dana Duricova, Viktor Komarek, Nadezda Machkova, Milan Lukas Background & Aim: Patients with stenosing and/or perforating type of Crohn's disease (CD) are at high risk of restenosis at the site of ileocolonic anastomosis and neoterminal ileum. The study was aimed to assess the efficacy and safety of endoscopic balloon dilatations in patients with newly developed anastomotic strictures. Methods: All endoscopic balloon dilatations performed in CD patients treated in our centre between 2007 and 2010 were retrospectively reviewed. Patients with anastomotic stricture who were dilated either for obstructive symptoms, or for incidental finding of endoscopically significant stenosis were included. Clinical data on symptoms before and after each dilatation, medication and outcome of each dilatation were retrieved from patients' files. Independent-Sample T test was used for statistical analysis with p<0.05 considered significant. Results: We enrolled 54 patients (mean age 40.5±12.8 years), in whom 86 dilatations were performed with the median followup of 28 months (range 10-39). Immediate endoscopic success of dilatation expressed by possibility to pass the scope through the stricture was achieved in 62% of procedures. Off 68 dilatations performed for obstructive symptoms clinical efficacy was observed after 65 (96%) sessions with the median duration of symptom-free interval of 14 months (range 231). Duration of the clinical effect was not affected by immediate endoscopic success (median 13 months in passable vs. 14 months in not passable dilatations, p = 0.48). Interestingly, patients treated with infliximab or adalimumab had a significantly shorter duration of the symptom-free period compared to those without biologicals (median 11 vs. 16.5 months, p = 0.04). No major complication was observed. Conclusions: Endoscopic balloon dilatation of the anastomotic Crohn's strictures is efficacious and safe alternative to repeated surgical resections. Clinical effect after dilatations seems to be independent on immediate endoscopic
Sa1325 Screening of TPMT Deficiency by Phenotyping and Genotyping: A Retrospective Study Among 1,500 IBD Patients in France Laurent Chouchana, Denis Roche, Celine Narjoz, Brigitte Pineau, Gilles Chatellier, Philippe H. Beaune, Marie-Anne Loriot Introduction: Thiopurines, 6-mercaptopurine and azathioprine, are immunosuppressive drugs largely prescribed in inflammatory bowel diseases (IBD). However, a wide interindividual variability in drug response, partly originated by a polymorphic activity of the thiopurine S-methyltransferase (TPMT), limits their use. Low TPMT activity is clearly associated with high risk of hematological toxicity, whereas very high TPMT activity could explain resistance. Historically, three groups of patients have been individualized into (i) low (deficient), (ii) intermediate or (iii) high TPMT activity, depending on carrying of two, one or no mutant allele, respectively. We report here our 8-year laboratory experience in TPMT phenotyping and genotyping. Materials & Methods: -TPMT phenotyping is assessed in red blood cells (RBC) using a reverse-phase HPLC method; high >8.5U (unit: nmol/h/8.108
S-281
AGA Abstracts
AGA Abstracts
Sa1323
2008;20:629). We hypothesized effectiveness of GMA and LMA might be dependent on depletion of granulocyte and monocytes. S100A12 was reported to be exclusively expressed in neutrophils and up-regulated by TNF α. The aim of this study was to investigate the changes of serum S100 A12 concentration in the GMA treatments and whether S100A12 increases the expression of adhesion molecules, CXCL and CCL chemokines. Methods; 24 patients with ulcerative colitis were treated with GMA. Serum S100A12 was estimated by ELISA methods. Clinical activity index (CAI) and serum CRP concentration were also checked. Immunohistochemical staining of S100A12 and receptor for advanced glication end products (RAGE) were performed in the operated specimens of patients with ulcerative colitis and with colonic carcinoma (control). HUVEC were seeded into 12 well plates and confluent plates were used to experiments. Each experiment was performed in triplicate. HUVEC were treated with human recombinant S100A12 protein. RNA was extracted by RNeasy Mini Kit. 1.5μg RNA was reverse-transcriptated into cDNA. ICAM-1, VCAM-1, IL-8, CCL-2 (MCP1), CCL5 (RANTES), CXCL9 (IP-10) and CXCL10 (Mig) mRNA was quantitated by realtime PCR. Results; S100A12 staining was faintly recognized in the mucosal layer of normal control. S100A12 staining was increased in infiltrating cells in inflamed colon in patients with ulcerative colitis. Strong staining was also recognized in crypt abscess. RAGE staining was also faintly recognized in the epithelial cells in nornmal control. However, RAGE staining was increased in the inflamed epithelial cells. Significantly serum S100A12 concentration was positively correlated with CAI (n=34, p=0.02, rs=0.404). 16 patients were able to estimate S100A12 concentration in the points of pre- and post-GMA treatment. 13 patients were GMA-responders and 3 patients were non GMA-responders. Serum S100A12 concentration was significantly decreased in GMA responders (pre- vs post- GMA, 1.34±1.08 vs 0.60±0.50, p<0.05). However, Serum S100A12 concentration of non GMA- responders was gradually increased with GMA treatments. ICAM-1, VCAM-1, IL-8, IP-10, Mig, MCP-1 and RANTES mRNA expressions were increased by S100A12 in HUVEC cell lines in time and dose-dependent manners. Conclusion; one of the mechanisms of GMA effect might be correlated with depletion of S100A12 by adsorption of activated neutrophils. S100A12 might aggravate acute and chronic inflammation by up-regulation of adhesion molecules, CXCL and CCL chemokines.
using MTX with a dosage of at least 15 mg/week at 6, 12, 24 and 60 months after initiation of MTX therapy and were considered to be in clinical remission, based on global physician's assessment, laboratory, radiological and/or endoscopic findings. Reasons for discontinuation of MTX were subclassified into adverse events, ineffectiveness, patient's request, pregnancy wish and others. Results: Seventy-eight CD-patients (57 females) were included. The median duration of IBD at initiating MTX therapy was 4 years (IQR 2-13 years) with a median age of 36 years (IQR 26-45 years). Fourty-eight patients (62%) initiated MTX therapy due to an adverse reaction to thiopurines, 17 patients due ineffectiveness of thiopurines, 3 patients had an adverse reaction to combination therapy of thiopurine and a biological and in 9 patients ineffectiveness of combination therapy. MTX therapy was discontinued in 49 patients (63%) after a median duration of 33 weeks (IQR 12-99 weeks) due to adverse events (35%), ineffectiveness (39%), patient's request (10%), pregnancy wish (8%), others (6%) and 1 unknown. Median duration of MTX use in the 29 patients who continued therapy was 162 weeks (IQR 101-231 weeks). In 8 of these 29 patients a biological agent was added after initiating MTX therapy due to ineffectiveness of monotherapy with MTX. The proportion of patients still using MTX at 6, 12, 24 and 60 months was, 73%, 59%, 44% and 9% respectively. Conclusion: After one year of MTX-therapy, effectiveness was established in 59 percent in CD patients. This percentage decreased to 9% after 5 years, mainly due to ineffectiveness or adverse reactions. Sa1319 To Determine the Relationship Between Time of Anti-TNFα Therapy Initiation and Anti-TNFα Dose Escalation Mindy Ching Wan Lam, Kenneth Atkinson, Brian Bressler BACKGROUND Factors which influence dose escalation for anti-tumor necrosis factor α (anti-TNF α) therapy in Crohn's disease (CD) are largely unknown. Approximately 50% of patients receiving anti-TNF therapy lose response for unclear reasons. Immunogenicity data does not suggest a coorelation to clinical response. The inflammatory burden in patients with CD is most early in the course of disease, and may influence the sustainability of infliximab therapy. AIM To determine if early initiation of anti-TNF α therapy will affect the need for dose escalation. METHOD This was a retrospective cohort study of biologic naïve patients on infliximab for Crohn's disease from 2 outpatient gastroenterology clinics during July 2009 to October 2010. All patients had moderately to severe CD (HBI > 8) Patients were divided into groups based on length of time between diagnosis to therapy initiation and concurrent immunosuppressant therapy. A Cox proportional hazards model was used to compare the time to dose escalation for the various groups. RESULTS Sixty eight patients comprised this cohort 53% males with an average age at diagnosis of 24.4±11.3 years, and average age of infliximab initiation of 33.7±14.8 years. Of the 68 patients, 29% initiated inflixiamb within two years of diagnosis, and 46% had concurrent immunosuppressant therapy at time of therapy initiation. There was a statistically significant lower probability of requiring dose esclataion in patients who initiated biologic therapy after two years but less than 12 years of diagnosis compared to those initiated within two years (p=0.049). Furthermore, the group whom therapy initation occurred within two years and not on immunosuppresant therapy had the highest probability of requiring dose escalation (p= 0.485). CONCLUSION Compared to patients diagnosed with Crohns disease greater than 2 years from initiating infliximab, those who receive infliximab within 2 years of diagnosis require more intense immunosuppressive therapy to avoid dose escalation. Strategies to avoid dose escalation must be studied. As suggested by this study, optimal induction thearpy (combined immunosuppressive therapy) in patients with a significant inflammatory burden is critical.
Sa1317 Fixed Weight Based Thiopurine Dosing Lowers Steroid Free Remission Rates in Crohn's Disease Chadwick I. Williams, Allen Greenwood, Evan Norris, Nadine Mokhallati, Gil Y. Melmed, Dermot P. McGovern, Marla Dubinsky Background: Thiopurine agents are commonly used to manage Crohn's disease (CD). Studies have shown that optimizing drug dosage based on therapeutic drug monitoring maximizes clinical benefit. Fixed weight-based dosing of thiopurine agents is often employed in clinical practice. Thiopurine metabolism, however, varies irrespective of weight. Fixed weight-based dosing can result in sub-optimal clinical outcomes. A previous study found that the 6 month steroid-free remission rate for patients on fixed weight-based thiopurine monotherapy was only 30 %. Titrating drug dose to achieve therapeutic metabolite (6-thioguanine [6-TGN] > 235) levels may improve steroid free remission rates in CD. Aims 1) Determine the frequency of patients achieving 6-TGN > 235 initiating standard weight based doses of thiopurines without dose escalation 2) determine the 6 month steroid free remission rate in patients achieving 6-TGN > 235. Methods: Clinical records of all pediatric CD patients seen at Cedars-Sinai Medical Center from August 2001- July 2010 were reviewed. Patients were eligible for inclusion if they were on standard weight-based doses of thiopurines (at least equivalent to 2.5mg/kg of azathioprine) at baseline. Patients were excluded if they had previous or on-going anti-TNF therapy, missing 6-TGN levels or low or absent thiopurine methyltransferase (TPMT) activity. Clinical data was collected at baseline and then every three months and included Harvey-Bradshaw index, steroid and thiopurine dose and laboratory indices. Thiopurine metabolite levels were routinely obtained 4-8 weeks after initiating standard dosing and again at 6 months. Results: Of the 102 total patients studied, only 24% initiating standard dosing did not undergo dose escalation (Group 1). These patients had a median initial 6TGN level of 288 and their 6-month steroid free remission rate was 42%. The remaining 76% of patients had at least one dose escalation (Group 2) based on a subtherapeutic initial 6TGN level (median=165). The 6-month steroid free remission rate in Group 2 was 51% with a median 6TGN level at 6 months of 313 vs 195 for those not in remission. One third of patients did not achieve remission with a 6-TGN level > 235. The mean dose of thiopurines in the group who underwent dose escalation was 3.4 mg/kg at 6 months. The average dose increase needed to achieve steroid free remission was 1.2 mg/kg. Only 8% of patients failed thiopurines due to drug toxicity. Conclusion: The majority of CD patients initiating standard weight based thiopurines dosing do not achieve therapeutic 6-TGN levels in the absence of dose escalation. This could explain reported suboptimal steroid free remission rates Prior to declaring a patient a thiopurine failure, dosing should be optimized so to maximize clinical benefit prior to switching to another class of therapy.
Sa1320 Sa1318 Response Evaluation and Safety of Thiopurines in the Treatment of Inflammatory Bowel Diseases (IBD) Giuseppe Costantino, Federica Furfaro, Alessandra Belvedere, Gionata Fiorino, Angela Alibrandi, Walter Fries
Effectiveness and Tolerability of Maintenance Methotrexate Therapy in Crohn's Disease Patients; Analysis of a Referral Hospital-Based 10-Years Intercept Cohort Margien L. Seinen, Nanne K. de Boer, Chris J. Mulder, Gerd Bouma, Adriaan A. van Bodegraven
Thiopurines (THIO) are widely used in inflammatory bowel disease (IBD). Besides adverse events (AE), the main drawbacks of THIO therapy are the slow onset of action and the difficulty to predict response to therapy. The aims of our study were to investigate predictors of response, efficacy, and safety of THIO therapy. METHODS: We analyzed the charts of IBD patients treated at our clinic with THIO. Harvey-Bradshaw index (HBI) or partial Mayo score (pMS) before and after 6,12,24 and 36 months of treatment with THIO were registered. Indications for treatment, disease duration, smoking status, and AE were recorded. AE were divided in early (within 4 wks), intermediate (from 2 to 6 months) and late (>6 months). A subgroup of patients with available data on C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), erythrocytes (RBC), mean corpuscular volume (MCV), leucocytes (WBC), neutrophils (NBC) prior to start of THIO and at 6 months was analyzed for predictors of clinical response. RESULTS: We identified 266 patients (157 CD, 109 UC) treated with
Background & Aim: Methotrexate (MTX) is a frequently administered immunomodulating drug for the treatment of Crohn's disease (CD). Unfortunately, limited longterm data are available. The aim of this study is to assess the maintenance effectiveness and tolerability of methotrexate (MTX) as maintenance therapy in Crohn's disease patients. Material and methods: A referral hospital-based, intercept cohort from January 1st, 2000, until January 1st, 2010 was explored to evaluate all consecutive MTX-using CD-patients. In this retrospective study, these patients were selected from a prospectively maintained database concerning all IBD-patients. MTX was initiated in patients after previous immunosuppressive therapies (mostly thiopurine, or combination with anti-TNFα), according to a step-up protocol. Therapeutic effectiveness was assessed by calculating the cumulative number of patients still
AGA Abstracts
S-280
THIO. Indications were steroid dependency, 71%, perianal fistulas, 4.5%, post-surgery recurrence, 8.3%, extensive disease, 13.6%, other, 2.3%. The mean disease duration was 5.3 yrs ± 8.7. The HBI and pMS fell significantly compared to pretreatment values at 6 months up to 3 yrs (all p<0.001 vs pre-treatment). Adverse events (AE) were analyzed on 733 patient-years. Overall 115 AE occurred in 87 patients (32.7%), 14 (16.1%) resolved with dose reduction, 70 patients (80.5%) discontinued THIO because of AE. We observed early AE in 41 patients, the most frequent were flu-like syndrome, 13.5%, nausea, vomiting or abdominal pain, 8.7%, pancreatic hyperenzymemia, 7.8%; intermediate AE in 16, the most frequent was hepatotoxicity (8.7%); late AE in 30, the most frequent were leucopenia, 9.6 %, infections, 7.8%, hepatotoxicity, 5.2%. For response analysis, data were available from 96 Responders (R) and 43 Non-R (NR). Clinical activity fell significantly in R (p<0.001, both CD and UC), but not in NR. Significant (p<0.001) drops were registered for CRP, ESR, WBC, and NBC in R, but only for WBC in NR. In both groups MCV increased significantly (p<0.001, both). Patients with shorter disease duration responded better to therapy (p=0.007). CONCLUSIONS: THIO are equally effective in CD and UC, maintaining efficacy over time. AE did occur in 32.7 % of patients leading to drug discontinuation in 26.3% of patients. Among late occurring AE, leucopenia, liver toxicity, and infections were the most frequent, emphasizing the need for continuous surveillance. CRP, ESR and NBC are useful markers to predict clinical response to thiopurines therapy in IBD patients, whereas the increase of MCV did not distinguish between N and NR. Early use of thiopurines was associated with better response to therapy.
success, whereas significantly shorter symptom-free interval was found in patients on biological therapy.
6-Thioguanine Measurement Allows Optimisation in Management of IBD Patients on Azathioprine Grace E. Dolman, Heather E. Johnson, Simon D. McLaughlin, Begley Joseph, Sean Weaver Introduction: Azathioprine is widely used in the management of Inflammatory Bowel Disease (IBD). The ideal dose for a patient is usually calculated by weight, but the rate of metabolism of azathioprine to its active metabolite 6-thioguanine (6TGN) varies between individuals. In addition, therapy may be limited by non-compliance, side effects or relapse of disease while on treatment. This retrospective study evaluates whether measuring 6TGN levels alters the management of patients on azathioprine for IBD. Methods: A search of laboratory records identified a cohort of 41 patients with IBD that had been tested for 6TGN levels. 48 tests had been performed as 7 patients were tested twice. Electronic and, when required, paper records were reviewed to record demographics and diagnosis. The reason for checking 6TGN level and how this altered management was evaluated. Results: The cohort was mainly young adults, with an age range of 18-73 years (median 36 years), and a slight female predominance (22F:19M). 66% of patients had Crohn's disease, the remainder Ulcerative Colitis (UC). Tests were performed because patients were symptomatic, suspected of non-compliance, had abnormal liver biochemistry or to confirm a therapeutic dose. Of the 48 tests performed, 12 (25%) identified low 6TGN levels. Compliance was addressed in 3 cases. Dose of azathioprine was increased in 6 cases and management was altered in 2 cases. 20 tests (42%) were within the therapeutic range and azathioprine dose was only increased following 3 of these tests. 4 patients required escalation of treatment to alternative medication or surgery. 16 tests (33%) were above the recommended level of 6TGN, despite all the patients receiving <2.7mg/kg of azathioprine and 4 patients receiving less than 2mg/kg. 5 patients with high 6TGN levels were subsequently switched to an alternative agent for maintenance therapy. 29 (60%) of all tests were performed on symptomatic patients to confirm adequate dosing before declaring a treatment failure. By weight calculation, 11 of these patients were receiving subtherapeutic doses of azathioprine. However, contrary to expectation, only 5 of 11 had low levels of 6TGN. Conclusion: Calculation of azathioprine dose by weight does not address individual variation in metabolism to the active component, 6TGN. In this retrospective study, management was altered in 51% of patients as a result of measuring 6TGN, with either alteration of dose, or change of therapy. The cost of the assay (£29/$50 US) limits its use, and currently we would recommend the use of 6TGN as a useful adjunct to established measures for azathioprine dose adjustment, such as clinical response and haematological indices.
Sa1321 Major Role of Sustained Drainage in the Management of Fistulizing Perianal Crohn's Disease Under Anti-TNF Therapy: A Cohort Study of 81 Patients With Successful Long Term Follow-up Audrey Haennig, Benoît Lepage, Ghislain Staumont, Philippe Otal, Jean Michel Suduca, Etienne Gorez, Patrick Faure, Guillaume Bonnaud, Barbara Bournet, Laurent Alric, Louis Buscail, Jean R. Escourrou, Jacques Moreau Perianal fistulas are one of major causes of disability in Crohn's disease. Medical treatment including biological therapies such as infliximab or adalumimab have been tried with varying degrees of success not exceeding roughly 40 to 50%. The aim of our study was to assess the efficacy and the specific role of biotherapy and local surgery on sustained fistula closure and to evaluate good and bad predicting factors in this field. Patients and methods: 81 patients (H: 39; F: 42; mean age: 31 years) with fistulizing perianal Crohn's disease were followed consecutively and prospectively. These patients are issued from a 10 years large regional cohort. Examination under anesthesia was performed in 95% patients. Fistulas were complex in 87% of cases. Luminal Crohn disease was severe (Harvey Bradshaw mean score=6). Median follow-up was 69 months. Anti-TNFα (mainly Infliximab) treatment was administered in 76.5% of patients. Seton drainage was realized in most cases (80.5%). Good response was defined as a complete fistula closure. Clinical and morphological data were subjected to simple and multivariate analysis. Log rank test estimates and Kaplan Meier curves were established with the main confounding factors. Results: Fistula closure was initially observed in 87.7% of cases after a median follow-up of 12.7 months. Setons were maintained for a median duration of 3.8 months. Fistula recurrence was observed in 47% of cases at a median time of 38.5 months (29% at one year). Twenty two reopened fistulas were redrained by using the same procedure for a median time of 4 months. Fistula closure after recurrence occurred in 66.8% of cases at a median time of 48 months. The global rate of healing in our study was then 73%. Multivariate analysis identified as the main poor prognostic factors: female gender, rectovaginal fistula, complex fistula, anal stenosis. Median duration of drainage was associated with good clinical response ahead the duration of biological therapy itself. Conclusion: Among this large cohort, prolonged seton placement and other local surgical procedures combined with infliximab resulted in complete healing in nearly ¾ of patients. These results are dramatically better than those that have been published until now. Whatever the biotherapy modalities, duration of drainage appears to be the best guarantee of long term success.
Sa1324 The Risk Factors of Surgical Recurrence in Patients With Crohn's Disease After First Intestinal Surgery Hyun Jin Jo, Kyu Joo Park, Mi Na Kim, Jong Pil Im, Sang Gyun Kim, Hyun Chae Jung, In Sung Song, Joo Sung Kim Backgrounds/Aims: Although the rate of surgery in patients with Crohn's disease (CD) is up to 80%, the risk factors for surgical recurrence except for smoking and penetrating disease behavior remain undetermined. The aim of this study was to identify clinical factors that influence the risk of surgical recurrence in CD patients. Methods: A total of 97 CD patients underwent first intestinal resection were consecutively enrolled from January 1985 to April 2010, and analyzed retrospectively. These patients were grouped according to the Montreal classification, and then clinical characteristics, medical treatment and type of surgery were analyzed. We obtained cumulative surgical recurrence rate and analyzed clinical predictors of surgical recurrence using Cox proportional hazards regression model. Results: A mean follow-up period after first intestinal resection was 91 (range: 1-449) months. Disease behavior at first operation was classified as penetrating type (51%), stricture type (33%), and non-penetrating/non-stricture type (16%). After first operation, 27 (28%) patients underwent second operation for the recurrence of CD. At second operation, concordance of disease behavior was found in 23 (85%) patients (OR 32.5, p<0.001). The overall cumulative reoperation rates at 1, 5, 10 and 15 years were 8%, 26%, 47% and 64%, respectively. In Cox regression analysis, delayed diagnosis (HR 1.023, 95% CI 1.010-1.035, p<0.001) and occurrence of perianal disease after first intestinal surgery (HR 4.267, 95% CI 1.176-15.483, p=0.027) were associated with increased risk of re-operation while diagnosis at old age (HR 0.942, 95% CI 0.896-0.991, p=0.021) was associated with decreased risk. Conclusions: Delayed diagnosis and perianal disease were risk factors of surgical recurrence in patients with CD.
Sa1322 Endoscopic Balloon Dilatation of Anastomotic Strictures in Patients With Crohn's Disease: Effect of Immediate Endoscopic Success and Biological Therapy Martin Bortlik, Eva Bouzkova, Dana Duricova, Viktor Komarek, Nadezda Machkova, Milan Lukas Background & Aim: Patients with stenosing and/or perforating type of Crohn's disease (CD) are at high risk of restenosis at the site of ileocolonic anastomosis and neoterminal ileum. The study was aimed to assess the efficacy and safety of endoscopic balloon dilatations in patients with newly developed anastomotic strictures. Methods: All endoscopic balloon dilatations performed in CD patients treated in our centre between 2007 and 2010 were retrospectively reviewed. Patients with anastomotic stricture who were dilated either for obstructive symptoms, or for incidental finding of endoscopically significant stenosis were included. Clinical data on symptoms before and after each dilatation, medication and outcome of each dilatation were retrieved from patients' files. Independent-Sample T test was used for statistical analysis with p<0.05 considered significant. Results: We enrolled 54 patients (mean age 40.5±12.8 years), in whom 86 dilatations were performed with the median followup of 28 months (range 10-39). Immediate endoscopic success of dilatation expressed by possibility to pass the scope through the stricture was achieved in 62% of procedures. Off 68 dilatations performed for obstructive symptoms clinical efficacy was observed after 65 (96%) sessions with the median duration of symptom-free interval of 14 months (range 231). Duration of the clinical effect was not affected by immediate endoscopic success (median 13 months in passable vs. 14 months in not passable dilatations, p = 0.48). Interestingly, patients treated with infliximab or adalimumab had a significantly shorter duration of the symptom-free period compared to those without biologicals (median 11 vs. 16.5 months, p = 0.04). No major complication was observed. Conclusions: Endoscopic balloon dilatation of the anastomotic Crohn's strictures is efficacious and safe alternative to repeated surgical resections. Clinical effect after dilatations seems to be independent on immediate endoscopic
Sa1325 Screening of TPMT Deficiency by Phenotyping and Genotyping: A Retrospective Study Among 1,500 IBD Patients in France Laurent Chouchana, Denis Roche, Celine Narjoz, Brigitte Pineau, Gilles Chatellier, Philippe H. Beaune, Marie-Anne Loriot Introduction: Thiopurines, 6-mercaptopurine and azathioprine, are immunosuppressive drugs largely prescribed in inflammatory bowel diseases (IBD). However, a wide interindividual variability in drug response, partly originated by a polymorphic activity of the thiopurine S-methyltransferase (TPMT), limits their use. Low TPMT activity is clearly associated with high risk of hematological toxicity, whereas very high TPMT activity could explain resistance. Historically, three groups of patients have been individualized into (i) low (deficient), (ii) intermediate or (iii) high TPMT activity, depending on carrying of two, one or no mutant allele, respectively. We report here our 8-year laboratory experience in TPMT phenotyping and genotyping. Materials & Methods: -TPMT phenotyping is assessed in red blood cells (RBC) using a reverse-phase HPLC method; high >8.5U (unit: nmol/h/8.108
S-281
AGA Abstracts
AGA Abstracts
Sa1323