Hélène Sarter

Methotrexate Is Not Superior to Placebo for Inducing Steroid-Free Remission, but Induces Steroid-Free Clinical Remission in a Larger Proportion of Patients With Ulcerative Colitis.

BACKGROUND & AIMS Parenteral methotrexate is an effective treatment for patients with Crohns disease, but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC. METHODS We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/wk) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe from 2007 through 2013. Patients were given prednisone (10 to 40 mg/d) when the study began and were randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary end point was steroid-free remission (defined as a Mayo score ≤2 with no item >1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤2 with no item >1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24. RESULTS Steroid-free remission at week 16 was achieved by 19 of 60 patients given methotrexate (31.7%) and 10 of 51 patients given placebo (19.6%)--a difference of 12.1% (95% confidence interval [CI]: -4.0% to 28.1%; P = .15). The proportion of patients in steroid-free clinical remission at week 16 was 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI: 1.1% to 35.2%; P = .04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group--a difference of 9.5% (95% CI: -7.5% to 26.5%; P = .28). No differences were observed in other secondary end points. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P = .03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P = .006). CONCLUSIONS In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC. ClinicalTrials.gov ID NCT00498589.

Incidence and Phenotype at Diagnosis of Very-early-onset Compared with Later-onset Paediatric Inflammatory Bowel Disease: A Population-based Study [1988-2011].

Background and Aims Very-early-onset inflammatory bowel disease [VEO-IBD] is a form of IBD that is distinct from that of children with an older onset. We compared changes over time in the incidence and phenotype at diagnosis between two groups according to age at IBD diagnosis: VEO-IBD diagnosed before the age of 6 years, and early-onset IBD [EO-IBD] diagnosed between 6 and 16 years of age. Methods Data were obtained from a cohort enrolled in a prospective French population-based registry from 1988 to 2011. Results Among the 1412 paediatric cases [< 17 years], 42 [3%] were VEO-IBD. In the VEO-IBD group, the incidence remained stable over the study period. In contrast, the incidence of EO-IBD increased from 4.4/105 in 1988-1990 to 9.5/105 in 2009-2011 [+116%; p < 10-4]. Crohns disease [CD] was the most common IBD, regardless of age, but ulcerative colitis [UC] and unclassified IBD were more common in VEO-IBD cases [40% vs 26%; p = 0.04]. VEO-IBD diagnosis was most often performed in hospital [69% vs 43%; p < 10-3]. Rectal bleeding and mucous stools were more common in patients with VEO-IBD, whereas weight loss and abdominal pain were more frequent in those with EO-IBD. Regarding CD, isolated colonic disease was more common in the VEO-IBD group [39% vs 14%; p = 0.003]. Conclusions In this large population-based cohort, the incidence of VEO-IBD was low and stable from 1988 to 2011, with a specific clinical presentation. These results suggest a probable genetic origin for VEO-IBD, whereas the increase in EO-IBD might be linked to environmental factors.

Postoperative Complications in Pediatric Inflammatory Bowel Disease: A Population-based Study.

Background:We describe, in a population-based cohort, the incidence of and factors associated with postoperative complications (POCs) in pediatric-onset inflammatory bowel disease. Methods:Using the pediatric population-based EPIMAD Cohort (1988–2004), among 692 incident inflammatory bowel disease cases, 128 patients with Crohns disease (CD) and 25 with ulcerative colitis (UC) (22%) had undergone at least 1 major abdominal surgery at a median age of 16 years [interquartile range, Q1–Q3 = 14–17]. Factors associated with POC were assessed using Cox models. Results:After a median postoperative follow-up of 8 years (3–12), 76 (49.7%) patients had experienced at least 1 POC with a total of 113 complications. The frequency of severe POC (grade >2) was similar in CD and UC (28% of all complications versus 27%, P = 0.95). A total of 64 early POCs (within 30 d of surgery) were observed in 47 patients (31%), with 33 being infectious and 31 noninfectious, higher in UC than in CD (25% of patients with CD versus 60% of patients with UC, P < 0.001). Forty-nine late POCs (≥30 d) were observed in 37 patients (24%). The occurrence of late POC was similar in UC and CD. The cumulative probability of POC was 31% (95% confidence interval, 24–39) at 1 month, 46% (38–54) at 1 year, and 48% (41–57) at 5 years. Multivariate analysis found that the UC type was the only factor associated with early POC (hazard ratio = 2.9; 95% confidence interval, 1.6–5.4). Conclusions:One-half of the children with inflammatory bowel disease had experienced at least 1 POC. Only UC relative to CD was significantly associated with an increased risk of early POC.

Growth Pattern in Paediatric Crohn Disease Is Related to Inflammatory Status.

Objectives: The respective role of disease activity and steroid therapy in growth impairment in paediatric-onset Crohn disease (CD) is still debated. Our aim was to investigate whether the growth pattern of children with CD was correlated with the inflammatory status during the disease course, regardless the cumulative duration of steroid therapy. Methods: One hundred and seven patients with a diagnosis of CD <17 years, followed during ≥2 years and for whom ≥2 height measures were available during follow-up, were identified between 1998 and 2010. Height, C-reactive protein (CRP), orosomucoid, and steroid therapy duration were collected at each visit. The relationship between the evolution of growth velocity and inflammatory status during follow-up was investigated using a linear mixed model with random coefficients. Results: Median age at diagnosis was 11.7 years (Q1–Q3: 9.8–13.5). Mean height for age (H/A) z score was 0.14 ± 1.29 at diagnosis and 0.05 ± 1.23 among the 75 patients who had reached their final height at maximal follow-up (median: 4.9 years; Q1–Q3: 3.8–6.4). Growth failure (H/A z score <−2) was present in 7 (8%) patients at diagnosis and 5 (5%) at maximal follow-up. Growth velocity was negatively correlated with the evolution of CRP (P < 0.0001) and orosomucoid (P < 0.0001) during follow-up. After adjustment for the cumulative duration of steroid therapy, these 2 correlations remained significant (CRP: P = 0.0008; orosomucoid: P < 0.0001). Conclusions: Children with CD with uncontrolled inflammatory status have a lower growth velocity. The inflammatory status should be kept as close to normal as possible in paediatric-onset patients with CD to optimize their growth pattern.

Efficacy and safety of adalimumab after infliximab failure in pediatric Crohn disease.

Objectives: The objective of the present study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with Crohn disease (CD) who experienced infliximab (IFX) failure at the population level. Methods: The present retrospective study included all of the children with CD from a pediatric-onset population-based cohort who received ADA before 18 years because of IFX failure or intolerance. Efficacy of ADA was evaluated using the physicians global assessment score, C-reactive protein and orosomucoid, and nutritional and growth indicators. Results: A total of 27 children with CD received ADA. Median age at CD diagnosis and at ADA initiation was 11 years (Q1 = 9; Q3 = 12) and 15 years (12; 15), respectively. After a median follow-up of 16 (8; 26) months after ADA initiation, ADA had clinical benefit as measured by the physical global assessment score in 19 patients (70%). Cumulative probability of failure to ADA treatment was 38% at 6 months and 55% at 1 year. Eight patients had a primary failure (30%) and 5 of 19 (26%) a secondary failure to ADA. Furthermore, 11 patients (40%) experienced a total of 19 adverse effects. No serious adverse effects were observed and none resulted in ADA discontinuation. There was no significant change in growth and nutritional patterns during the study period, but we found a significant decrease in median C-reactive protein (15 mg/L [4; 44] vs 9 mg/L [3; 19]; P = 0.05) and orosomucoid (1.6 g/L [1.5; 2.6] vs 1.1 g/L [0.8; 1.9]; P = 0.001) from ADA initiation to maximal follow-up in patients responding to ADA. Conclusions: In the present population-based cohort of pediatric-onset CD with IFX failure, treatment with ADA was safe and effective in two-thirds of patients.

Previous Exposure to Multiple Anti-TNF Is Associated with Decreased Efficiency in Preventing Postoperative Crohn’s Disease Recurrence

Background and Aims Infliximab and adalimumab are increasingly used to prevent postoperative recurrence in Crohns disease patients. The impact of previous exposure to one or more anti-tumour necrosis factor [TNF] agents before surgery on the efficacy of anti-TNF therapy on postoperative recurrence is unknown. Methods We performed a retrospective analysis of Crohns disease patients who underwent surgical bowel resection with anastomosis and prophylactic treatment with anti-TNF therapy between January 2005 and June 2013. Results A total of 57 consecutive Crohns disease patients with bowel resection and anastomosis followed by prophylactic treatment with anti-TNF were included; 21 [37%] and 24 [42%] patients had a previous exposure to one and more than one anti-TNF agents, respectively; 39 patients [68%] had a surveillance colonoscopy. Cumulative rates of postoperative endoscopic recurrence at 2 years were 45.5% [26.6-69.6%] in patients exposed to two or more anti-TNFα as compared with 29.1% [11.5-48.1%] in patients exposed to one or to zero anti-TNFα before surgery [p = 0.07]. Cumulative rates of clinical recurrence at 1 year were 21.6% [9.6-44.4%] in patients exposed to two or more anti-TNFα as compared with 6.9% [1.8-25.1%] in patients exposed to zero or one anti-TNFα before surgery [p = 0.02]. Multivariable analysis identified smoking and previous exposure to two or more anti-TNFα as risk factors for Crohns disease clinical or endoscopic postoperative recurrence (hazard ratio [HR] = 3.17; 95% confidence interval [CI]: 1.3-7.8, p = 0.01 and HR = 4.2; 95% CI: 1.8-10.2, p = 0.001, respectively). Conclusions Previous exposure to two or more anti-TNF agents was associated with a higher risk of postoperative recurrence in Crohns disease patients.

Independent Validation of a Self-Report Version of the IBD Disability Index (IBDDI) in a Population-Based Cohort of IBD Patients

Introduction A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Methods Persons 18-65 years old from the population-based University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We used Pearson correlation coefficients to assess construct validity, Cronbachs alpha to assess internal consistency, and Factor analysis to assess which of the IBDDI items likely belonged to a single IBD-related disability factor. Results In response to the survey request,1143 (46% of those contacted) participated (61% female, mean age 51, 52% with Crohns disease). On an index scale from 0-100, 14% had a score ≥50 (extreme disability, 18% of those with Crohns disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an inverse correlation with IBDQ (-0.86). The Cronbachs alpha was high (0.88). All but 2 items (number of liquid stools in the past week and arthritis/arthralgia) of the 14 identified for IBDDI loaded highly onto a single factor (factor loading > 0.40). Conclusions The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

DOP037 Long-term outcome of paediatric-onset ulcerative colitis: early years are shaping the future

Data on long-term outcome of paediatric-onset ulcerative colitis (UC) are scarce. Methods: All patients recorded by the EPIMAD Registry between 1988 and 2004 with a diagnosis of UC before the age of 17 years were included. The cumulative risks of receiving immunosuppressants (IS, including azathioprine and/or methotrexate and/or cyclosporine) and antiTNFα therapy, as well as undergoing colectomywere estimated via the Kaplan-Meier method. Results: 159 paediatric-onset UC patients with a follow-up ≥ 2 years were identified (5% of all cases of UC), including 92 females. Median age at diagnosis was 14.5 years [IQR: 11.4-16.1] and median duration of follow-up was 11.5 years [8.2-15.8]. At diagnosis 25% of children had proctitis (E1), 38% left-sided colitis (E2) and 37% extensive colitis (E3). Disease course was characterised by disease extension in 50% of patients (50 among 101 E1 and E2). Cumulative risks of colonic extension were 11% at 1 year, 48% at 5 years, 54% at 10 years and 57% at 15 years. At diagnosis 12 (7.6%) patients had extra intestinal manifestations and 40 (25%) at maximal follow-up including articular manifestations (n= 27). Cumulative probabilities of receiving IS and anti-TNFα therapy were respectively 20% and 0.5% at 2 years, 28% and 4% at 5 years, 32% and 7% at 10 years and 35% and 13% at 15 years. Cumulative probabilities of colectomy were 6% at 1 year, 20% at 5 years, 21% at 10 years and 24% at 15 years. Conclusions: In this large population-based cohort of paediatric-onset UC disease the rate of disease extension and colectomy rapidly increased within the first 6 years after diagnosis and then remained stable. These data emphasize the need for early intervention to modify the natural history of paediatric UC.

Su1924 Incidence and Phenotype at Diagnosis in Very Early Compared to Later-Onset Pediatric Inflammatory Bowel Disease: A Population-Based Study (1988-2011)

1 Gastroentérologie pédiatrique, Université et CHRU de Lille, 2 Epidémiologie, Université et CHRU de Lille, 3 Gastroentérologie, Université et CHU d’Amiens, 4 Gastroentérologie, Université et CHU de Rouen, 5 Gastroentérologie, Université et CHRU de Lille, 6 Unité de Pédiatrie, Hôpital St Vincent, Faculté Catholique de Lille, 7 Gastroentérologie, Hôpital Les Bonnettes d’Arras, 8 Gastroentérologie, Université et CHRU de Nancy, 9 LIRIC UMR 995 Inserm , Université Lille 2 / CHRU de Lille, France.

Tu1337 Anti-TNFα Treatment Efficacy in Prevention of Postoperative Recurrence in Crohn's Disease Depends on Previous Exposure to Anti-TNFα Agents

Background Almost 50% of Crohns disease (CD) patients will need surgical resection during their follow-up. Infliximab and adalimumab are effective to prevent postoperative recurrence in CD patient naive from anti-TNFα antibodies (anti-TNF). The effect of previous exposure to one or more anti-TNF before surgery on prevention of post-operative recurrence by these agents is still unknown. The aim of our study was to investigate the efficacy of anti-TNF to prevent CD post-operative recurrence according to previous exposure to these drugs. Methods: We performed a retrospective analysis of CD patients, followed in a tertiary referral centre, who underwent surgical bowel resection and prophylactic treatment with anti-TNF between January 2005 and June 2012. Infliximab, adalimumab and certolizumab pegol were considered as prophylactic treatments if started within threemonths after surgery. Endoscopic recurrence, defined as a Rutgeerts score ≥ i2 and clinical recurrence, defined as physician judgment were evaluated one year after surgery and also during the follow-up. Results: Fifty-seven consecutive CD patients with bowel resection, anastomosis and prophylactic treatment with anti-TNF were included in the study. Twenty two patients (39%) had prior intestinal resection for CD and a majority (45, 79%) were treated with at least one antiTNF before surgery. Twenty-four (42%) received two or more anti-TNF before surgery and 12 (21%) patients were naive from anti-TNF. Thirty-nine (67%) patients had a surveillance colonoscopy one year after surgery. At one year, the global endoscopic and clinical postoperative recurrence rates were 42% (17/39) and 19% (11/57), respectively. According to previous exposure to anti-TNF, patients with two or more anti-TNF before surgery had a higher oneyear endoscopic recurrence rate compared with patients that received one and zero antiTNF before surgery (62%, n=13/21 vs. 31%, n=4/13 vs. 20%, n=1/5). Also, patients with two or more anti-TNF before surgery had a higher rate of clinical recurrence compared with patients receiving less than two anti-TNF before surgery (37%, n=9/24 vs. 12%, n=4/33, p=0.05). In multivariate analysis, smoking (HR=3.2; IC 95%: 1.2-7.8) and previous exposure to two or more anti-TNF (HR=4.3; IC 95%: 1.3-14.0) were significantly associated to the risk of clinical postoperative recurrence in CD patients. Conclusion: Previous exposure to two or more anti-TNF agents was associated to a higher risk of postoperative recurrence in CD patients receiving prophylactic treatment with anti-TNF. This study suggested that previous exposure to anti-TNF should be taken into account when managing prevention of post-operative recurrence in CD patients.