J.-F. Colombel

Early development of stricturing or penetrating pattern in Crohn’s disease is influenced by disease location, number of flares, and smoking but not by NOD2/CARD15 genotype

Background: Crohn’s disease is a heterogeneous entity. Disease behaviour, characterised as stricturing, penetrating, or non-stricturing non-penetrating, is a clinically important phenotype as it is associated with complications and need for surgery. It has recently been showed that the behaviour of Crohn’s disease changes over the course of the disease. Aim: To assess the association between rapid development of a penetrating or stricturing pattern of Crohn’s disease and demographic and clinical characteristics as well as NOD2/CARD15 genotype. Patients and methods: A total of 163 patients with a firm diagnosis of Crohn’s disease and who had non-penetrating non-stricturing disease at diagnosis were studied. Various demographic and clinical characteristics as well as antisaccharomyces cerevisiae antibody status and NOD2/CARD15 genotype were documented in these patients. These characteristics were compared in subgroups of patients according to evolution of disease behaviour five years after diagnosis. Results: Five years after diagnosis there were 110 (67.5%) patients with non- structuring non-penetrating disease, 18 (11%) with stricturing disease, and 35 (21.5%) with penetrating disease. In multivariate analysis, only disease location and number of flares per year were significantly discriminant between the three subgroups (p=0.0009 and 0.0001, respectively). Ileal location of the disease was associated with a stricturing pattern while a high number of flares was associated with a penetrating pattern. Active smoking was also associated with a penetrating pattern compared with a non-stricturing non-penetrating pattern only. Conclusions: Early development of stricturing or penetrating behaviour in Crohn’s disease is influenced by disease location, clinical activity of the disease, and smoking habit, but not by NOD2/CARD15 genotype.

A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn's disease. Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives (GETAID).

OBJECTIVE:The aim of this randomized controlled study was to investigate the efficacy of ciprofloxacin compared with mesalazine in treating active Crohns disease.METHODS:Patients with a mild to moderate flare-up of Crohns disease (mean Crohns Disease Activity Index [CDAI]; 217; range, 160–305) were randomized to receive ciprofloxacin 1 g/day or Pentasa 4 g/day for 6 wk. Complete remission was defined at wk 6 as a CDAI ≤ 150 associated with a decrease (Δ) in CDAI > 75. Partial remission was defined as a CDAI ≤ 150 with 50 < Δ CDAI < 75 or a CDAI > 150 with Δ CDAI > 50 at wk 6. Group sequential procedure with triangular continuation regions was used to monitor the trial through the difference in complete remission rates, every 20 patients included.RESULTS:Inclusion of patients was stopped at the second step, i.e., after 40 inclusions, with the conclusion of no difference in complete remission rates between ciprofloxacin- and Pentasa-treated groups. Among the 18 patients taking ciprofloxacin, two decided to stop treatment during the trial and three were considered as treatment failures because of deterioration at wk 3. Among the 22 patients taking mesalazine, one patient was lost to follow-up and eight patients were considered as treatment failures. Complete remission was observed in 10 patients (56%) treated with ciprofloxacin and 12 patients (55%) treated with mesalazine and partial remission was observed in three and one patient, respectively.CONCLUSIONS:This study suggests that ciprofloxacin 1 g/day is as effective as mesalazine 4 g/day in treating mild to moderate flare-up of Crohns disease.

Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease

Aim : To test the hypothesis of an association between polymorphism in FCGR3A (the gene coding for FcγRIIIa, which is expressed on macrophages and natural killer cells, is involved in antibody‐dependent cell‐mediated cytotoxicity and has recently been associated with a positive response to rituximab, a recombinant immunoglobulin G1 antibody used in non‐Hodgkins lymphomas) and response to infliximab in Crohns disease.

Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine

Aim: To assess the characteristics and clinical course of nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease treated with azathioprine, so as to estimate the frequency of this complication and search for risk factors. Methods: Cases were identified through a systematic survey of patients followed at 11 centres. At one centre, the cumulative risk of NRH was estimated and a case–control study was undertaken to identify risk factors. Results: 37 cases of NRH (30 male, 7 female) were identified between 1994 and 2005. The median dose of azathioprine was 2 mg/kg/d (range 1.5 to 3.0). The median time between the start of azathioprine and the diagnosis of NRH was 48 months (range 6 to 187). After a median follow up period of 16 months (range 1 to 138), 14 patients developed complications of portal hypertension. Using multivariate analysis, male sex and stricturing behaviour were the two risk factors associated with NRH in patients treated with azathioprine. The cumulative risk calculated from the database (one centre) was 0.5% at 5 years (95% confidence interval, 0.11 to 0.89) and 1.25% at 10 years (0.29 to 2.21). Conclusions: NRH is a rare but potentially severe complication of azathioprine in patients with inflammatory bowel disease. Clinicians should be aware of this complication, and should monitor liver function tests and platelet counts closely in their patients.

A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease (CD). Patients and methods: Forty five patients with a CD activity index (CDAI) of 250–450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn’s disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

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

The efficacy and safety of a third anti-TNF monoclonal antibody in Crohn’s disease after failure of two other anti-TNF antibodies

Background  Adalimumab (ADA) and certolizumab pegol (CZP) have demonstrated efficacy in Crohn’s disease (CD) patients previously treated with infliximab (IFX).

One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2

Patients with moderately‐to‐severely active ulcerative colitis (UC) are unlikely to continue anti‐TNF therapy in the absence of early therapeutic response.

Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis

OBJECTIVES:Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX.METHODS:This was a retrospective survey of patients seen during the period 2000–2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed.RESULTS:A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (±s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (±s.e.) was 61.3±5.3% at 3 months and 41.3±5.6 % at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy.CONCLUSIONS:In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.

Tioguanine in patients with Crohn's disease intolerant or resistant to azathioprine/mercaptopurine.

Background:  Tioguanine (TG) is an antimetabolite which may be regarded as an alternative to azathioprine (AZA)/mercaptopurine (MP) in patients with inflammatory bowel diseases.