Guillaume Savoye

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohns disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS We performed a prospective study of 115 patients with Crohns disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS Approximately 50% of patients with Crohns disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Ciclosporin versus infliximab in patients with severe ulcerative colitis refractory to intravenous steroids: a parallel, open-label randomised controlled trial

BACKGROUND Ciclosporin and infliximab are potential rescue treatments to avoid colectomy in patients with acute severe ulcerative colitis refractory to intravenous corticosteroids. We compared the efficacy and safety of these drugs for this indication. METHODS In this parallel, open-label, randomised controlled trial, patients were aged at least 18 years, had an acute severe flare of ulcerative colitis defined by a Lichtiger score greater than 10 points, and had been given an unsuccessful course of high-dose intravenous steroids. None of the patients had previously received ciclosporin or infliximab. Between June 1, 2007, and Aug 31, 2010, patients at 27 European centres were randomly assigned (via computer-derived permutation tables; 1:1) to receive either intravenous ciclosporin (2 mg/kg per day for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg on days 0, 14, and 42). In both groups, azathioprine was started at day 7 in patients with a clinical response. Neither patients nor investigators were masked to study treatment. The primary efficacy outcome was treatment failure defined by absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Analysis was by intention to treat. This trial is registered with EudraCT (2006-005299-42) and ClinicalTrials.gov (NCT00542152). FINDINGS 115 patients were randomly assigned; 58 patients were allocated to receive ciclosporin and 57 to receive infliximab. Treatment failure occurred in 35 (60%) patients given ciclosporin and 31 (54%) given infliximab (absolute risk difference 6%; 95% CI -7 to 19; p=0·52). Nine (16%) patients in the ciclosporin group and 14 (25%) in the infliximab group had severe adverse events. INTERPRETATION Ciclosporin was not more effective than infliximab in patients with acute severe ulcerative colitis refractory to intravenous steroids. In clinical practice, treatment choice should be guided by physician and centre experience. FUNDING Association François Aupetit, Société Nationale Française de Gastroentérologie, and the International Organization for the study of Inflammatory Bowel Disease.

The natural history of pediatric ulcerative colitis: a population-based cohort study.

OBJECTIVES:The natural history of ulcerative colitis (UC) has been poorly described in children.METHODS:In a geographically derived incidence cohort diagnosed from 1988 to 2002, we identified 113 UC patients (age 0–17 years at diagnosis) with a follow-up of at least 2 years. The cumulative risk of colectomy was estimated by the Kaplan–Meier method. Risk factors for disease extension were assessed with logistic regression models, and risk factors for colectomy with Cox hazards proportional models.RESULTS:Median follow-up time was 77 months (46–125). At diagnosis, 28% of patients had proctitis, 35% left-sided colitis, and 37% extensive colitis. Disease course was characterized by disease extension in 49% of patients. A delay in diagnosis of more than 6 months and a family history of inflammatory bowel disease were associated with an increased risk of disease extension, with odds ratios of 5.0 (1.2–21.5) and 11.8 (1.3–111.3), respectively. The cumulative rate of colectomy was 8% at 1 year, 15% at 3 years, and 20% at 5 years. The presence of extra-intestinal manifestations (EIMS) at diagnosis was associated with an increased risk of colectomy (hazard ratio (HR)=3.5 (1.2–10.5)). Among the patients with limited disease at diagnosis, the risk of colectomy was higher in those who experienced disease extension than in those who did not (HR=13.3 1.7–101.7).CONCLUSIONS:Pediatric UC was characterized by widespread localization at diagnosis and a high rate of disease extension. Twenty percent of children had their colon removed after 5 years. The colectomy rate was influenced by disease extension and was associated with the presence of EIMS at diagnosis.

Early administration of azathioprine vs conventional management of Crohn's Disease: a randomized controlled trial.

BACKGROUND & AIMS Immunomodulator therapy is effective for patients with Crohns disease (CD) but has not been shown to affect disease progression, presumably because it is given too late after diagnosis. We compared the efficacy of early treatment (within 6 months after diagnosis) with azathioprine versus conventional management of patients at high risk for disabling disease. METHODS We performed an open-label trial of adults with a diagnosis of CD for less than 6 months who were at risk for disabling disease. From July 2005 to November 2010, patients at 24 French centers were randomly assigned to treatment with azathioprine (2.5 mg ∙ kg(-1) ∙ day(-1), n = 65) or conventional management (azathioprine only in cases of corticosteroid dependency, chronic active disease with frequent flares, poor response to corticosteroids, or development of severe perianal disease) (n = 67). The primary end point was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission during the first 3 years after inclusion. RESULTS During the 3-year follow-up period, 16 patients in the azathioprine group were switched to mercaptopurine or methotrexate therapy because of intolerance or poor efficacy. Forty-one patients in the conventional management group required immunosuppressant therapy (61%; median time to first prescription, 11 months). In the azathioprine group, a median 67% of trimesters were spent in remission (interquartile range, 11%-85%) compared with 56% in the conventional management group (interquartile range, 29%-73%) (P = .69). Among secondary outcomes, a higher cumulative proportion of patients in the azathioprine group were free of perianal surgery than in the conventional management group (96% ± 3% and 82% ± 6% at month 36, respectively; P = .036). The cumulative proportion of patients free of intestinal surgery and anti-TNF therapy did not differ between groups. CONCLUSIONS Based on results from a clinical trial, administration of azathioprine within 6 months of diagnosis of CD was no more effective than conventional management in increasing time of clinical remission. Clinicaltrials.gov, Number NCT00546546.

European consensus on the diagnosis and management of iron deficiency and anaemia in inflammatory bowel diseases

European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases

Natural history of elderly-onset inflammatory bowel disease: a population-based cohort study

Data on the natural history of elderly-onset inflammatory bowel disease (IBD) are scarce. Methods In a French population-based cohort we identified 841 IBD patients >60 years of age at diagnosis from 1988 to 2006, including 367 Crohns disease (CD) and 472 ulcerative colitis (UC). Results Median age at diagnosis was similar for CD (70 years (IQR: 65–76)) and UC (69 years (64–74)). Median follow-up was 6 years (2–11) for both diseases. At diagnosis, in CD, pure colonic disease (65%) and inflammatory behaviour (78%) were the most frequent phenotype. At maximal follow-up digestive extension and complicated behaviour occurred in 8% and 9%, respectively. In UC, 29% of patients had proctitis, 45% left-sided and 26% extensive colitis without extension during follow-up in 84%. In CD cumulative probabilities of receiving corticosteroids (CSs), immunosuppressants (ISs) and anti tumor necrosis factor therapy were respectively 47%, 27% and 9% at 10 years. In UC cumulative probabilities of receiving CS and IS were 40% and 15%, respectively at 10 years. Cumulative probabilities of surgery at 1 year and 10 years were 18% and 32%, respectively in CD and 4% and 8%, respectively in UC. In CD complicated behaviour at diagnosis (HR: 2.6; 95% CI 1.5 to 4.6) was associated with an increased risk for surgery while CS was associated with a decreased risk (HR: 0.5; 0.3 to 0.8). In UC CS was associated with an increased risk (HR: 2.2; 1.1 to 4.6) for colectomy. Conclusions Clinical course is mild in elderly-onset IBD patients. This information would need to be taken into account by physicians when therapeutic strategies are established.

The changing pattern of Crohn’s disease incidence in northern France: a continuing increase in the 10‐ to 19‐year‐old age bracket (1988–2007)

Aliment Pharmacol Ther 2011; 33: 1133–1142

Value of wireless capsule endoscopy in patients with indeterminate colitis (inflammatory bowel disease type unclassified)

Background Wireless capsule endoscopy (WCE) can identify small bowel mucosal lesions not seen with other imaging modalities. This technique can therefore play an important diagnostic role in the evaluation of patients with inflammatory bowel disease type unclassified (IBDU). We report on a multicentric study whose objective was to evaluate the value of WCE to increase diagnostic accuracy in categorizing IBDU. Methods Thirty patients with IBDU and negative serology were included. WCE was performed with a standard Pillcam capsule. Outcome measures were classified as suggestive of Crohns disease (CD) when ≥3 ulcerations were present. Results WCE displayed endoscopic features suggestive for CD in 5 patients. In 6 other patients, WCE was negative, but repeated ileocolonoscopy with biopsies performed during follow‐up evaluation revealed CD in 5 and ulcerative colitis (UC) in 1 patient. UC was found in a seventh case at colectomy performed just after WCE. Eighteen patients remained with a diagnosis of IBDU 16 months on average after WCE. Conclusions WCE is a potentially clinically useful technique for categorizing a subgroup of patients with IBDU, although negative WCE does not exclude further diagnosis of CD. Patients with negative WCE who remain IBDU at follow‐up evaluation may belong to an original subgroup of IBD. (Inflamm Bowel Dis 2006)

Epidemiology of inflammatory bowel diseases: New insights from a French population-based registry (EPIMAD)

Most data regarding the natural history of inflammatory bowel diseases and their therapeutic management are from tertiary referral-centres. However, the patients followed in these centres represent a selected sample and extrapolation of these data to the general population is disputable. The EPIMAD Registry covers a large area of Northern France with almost 6 million inhabitants representing 9.3% of the entire French population. From 1988 to 2008, 18,170 incident patients were recorded in the registry including 8071 incident Crohns disease, 5113 incident ulcerative colitis and 591 unclassified inflammatory bowel disease cases. The aim of this study was to review some of the most recent information obtained from this large population-based registry since its launch in 1988.

An α-Linolenic Acid-Rich Formula Reduces Oxidative Stress and Inflammation by Regulating NF-κB in Rats with TNBS-Induced Colitis

We have previously shown that α-linolenic acid (ALA), a (n-3) PUFA exerts in vitro antiinflammatory effects in the intestine. In this study, we aimed to evaluate its effect on inflammatory and oxidative stress in a colitis model. Colitis was induced in 2 groups at d 0 by intrarectal injection of 2-4-6-trinitrobenzen sulfonic acid (TNBS), whereas the control group received the vehicle. Rats we fed 450 mg . kg(-1) . d(-1) of ALA (TNBS+ALA) while the other colitic group (TNBS) and the control group were fed an isocaloric corn oil formula for 14 d (from d -7 to d 7). RBC fatty acid composition was assessed. Oxidative stress was studied by measuring urinary 8-isoprostanes (8-IP) and colon glutathione (GSH) concentration and inducible nitric oxide synthase (iNOS) expression. Colitis was assessed histologically, by production of proinflammatory mediators, including cytokines, leukotrienes B(4) (LTB(4)), and cyclooxygenase-2 (COX-2) and by nuclear factor-κB (NF-κB) activation. The ALA-rich diet significantly increased the RBC levels of ALA, eicosapentaenoic acid, and docosapentaenoic acid (n-3) compared with the TNBS group (P < 0.01 for all). The beneficial effect of ALA supplementation on oxidative stress was reflected by lower urinary 8-IP levels (P < 0.05), a normalized colon GSH concentration (P < 0.01), and reduced colon iNOS expression (P < 0.05) compared with the TNBS group. ALA also protected against colon inflammation as assessed by lower tumor necrosis factor-α secretion and mRNA level (P < 0.05), reduced NF-κB activation (P = 0.01), and lower colon lipid mediator concentrations such as LTB(4) and COX-2 (P < 0.05) compared with the TNBS group. These findings show that an ALA-rich formula is beneficial to TNBS-induced colitic rats via inhibition of oxidative and inflammatory stress.