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Background: Azathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD)., Aim: To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations., Methods: This multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16 weeks. In the weight-based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT) or 2.5 mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8 × 10(8) red blood cells (RBC), or to a maximal dose of 4 mg/kg/day., Results: After randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P = 0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P = 0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10(8) RBC respectively (P = 0.07)., Conclusions: Despite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm. [Clinicaltrials.Gov Identifier Nct00113503]., (© 2013 John Wiley & Sons Ltd.)

Background: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy., Aim: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed., Methods: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab., Results: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy., Conclusions: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials., (© 2013 John Wiley & Sons Ltd.)

Background: Recent genome-wide association studies based on adult and paediatric populations have implicated >30 genes/loci as susceptibility loci for Crohn's disease (CD)., Aims: To investigate whether reported genes/loci were also associated with CD in Canadian children., Design and Methods: A case-control design was implemented at three paediatric gastroenterology clinics in Canada. Children < or =18 years of age with a confirmed diagnosis of CD were recruited along with controls. Single nucleotide polymorphisms (SNPs) in five genome-wide association studies reported genes/loci were genotyped. Associations between individual SNPs and CD were examined., Results: A total of 406 cases and 415 controls were studied. The mean (+/-s.d.) age of the cases was 12.3 (+/-3.2) years. Most cases were male (56.6%), had ileo-colonic disease (L3 +/- L4, 52.0%) and inflammatory behaviour (B1 +/- p, 86.9%) at diagnosis. Allelic association analysis (two-tailed) showed that three of the five targeted SNPs were significantly associated with overall susceptibility for CD (ZNF365, r10995271, P = 0.001; PTPN2, rs1893217, P = 0.005; STAT3, rs744166, P = 0.01). Associations with SNP rs4613763 in the PTGER4 locus were marginally nonsignificant (P = 0.07). The ZNF365 and STAT3 SNPs were predominantly associated with ileal disease with or without colonic involvement., Conclusion: The identified susceptibility genes/loci for adult-onset CD also confer risk for paediatric-onset CD.

Background: A recent genome-wide association study in adult patients with ulcerative colitis (UC) has implicated the interleukin 10 (IL-10) gene as an important candidate gene. Moreover, a UC-associated single nucleotide polymorphism (SNP) rs3024405 was also significantly associated with adult Crohn's disease (CD)., Aims: To examine whether IL-10-CD associations extended to paediatric-onset CD., Methods: We implemented the case-control design at three paediatric gastroenterology clinics in Canada. CD patients (

Background: Despite its pivotal role in mucosal inflammation, data on TNFalpha levels in inflammatory bowel diseases have been contradictory., Aim: To examine TNFalpha production in relation to the type and severity of inflammation and therapy, using colonic explant cultures., Materials and Methods: Rectal mucosal biopsies from 271 paediatric patients (178 inflammatory bowel disease, 27 inflammatory controls, 66 normal) were cultured for 4 or 18 h. Basal TNFalpha tissue content and release into the medium were measured by ELISA and compared to histological severity and clinical parameters., Results: TNFalpha release as well as tissue-associated TNFalpha levels were significantly increased in rectal biopsies from involved inflammatory bowel disease tissue. The amount of TNFalpha correlated with inflammation severity scores. TNFalpha levels were higher at 18 compared to 4 h in all groups, whether inflamed or not. TNFalpha released from rectal biopsies was lower among treated patients at 18 h. The presence of proximal colonic involvement was associated with higher TNFalpha release by uninvolved Crohn's disease rectal biopsies compared to patients with ileitis alone., Conclusions: TNFalpha production and release is increased in involved rectal explants from inflammatory bowel disease. Anti-inflammatory treatment diminishes this response.

Background: In the presence of inflammation, an increased expression of enterocyte MHC class II is observed, leading to altered mucosal antigen handling. Corticosteroids are potent anti-inflammatory drugs, widely used in treating inflammatory bowel disorders. However, their diverse mechanisms of action are only partially understood., Aim: To evaluate effect and mechanisms of corticosteroids on intestinal crypt epithelial cell MHC class II., Methods: The effect of dexamethasone treatment on cytokine-induced MHC class II expression was measured in IEC-6 cells by immunofluorescence and flow cytometry. To determine the role of the TGF-beta1 regulatory pathway in mediating the effects of dexamethasone, neutralizing anti-TGF-beta antibodies were used. Additionally, endogenous and dexamethasone-stimulated IEC-6 cell TGF-beta1 production was measured by ELISA., Results: Dexamethasone potently down-regulated IFNgamma-induced class II expression on IEC-6 cells, in a dose-dependent manner. TGF-beta1 had a similar inhibitory effect on class II expression. However, neutralizing anti-TGF-beta antibodies did not alter the effect of dexamethasone. Furthermore, dexamethasone reduced endogenous TGF-beta1 synthesis., Conclusions: Corticosteroids inhibit cytokine-induced MHC class II expression on IEC-6 cells in a TGF-beta1 independent way. This effect may markedly alter enterocytic antigen presentation, reducing the aberrant state of activation of mucosal immune cells.