Multiple functional variants at the 3p21 locus contribute to ulcerative colitis: Results from a European consortium

in Journal of Crohn’s and Colitis [=JCC] (2012, February)

The impact of infliximab therapy on intestinal mucosal gene expression of endothelial cell adhesion molecules in patients with inflammatory bowel disease

in Gastroenterology (2010), 138(5 Suppl I), -677

Mucosal gene signatures to predict response to infliximab in patients with ulcerative colitis

in Gut (2009), 58(12), 1612-9

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti ... [more ▼]

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor alpha (anti-TNFalpha) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis. METHODS: Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data. RESULTS: For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity. CONCLUSION: Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis. ClinicalTrials.gov number, NCT00639821. [less ▲]

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort

in Gut (2009), 58(4), 492-500

BACKGROUND AND AIMS: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow ... [more ▼]

BACKGROUND AND AIMS: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27-83). METHODS: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. RESULTS: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. CONCLUSIONS: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery. [less ▲]

TECK and MADCAM-1 mucosal expression in active IBD: the effect of infliximab therapy

in Gastroenterology (2009), 136

The impact of infliximab therapy on colonic mucosal expression of barrier genes in patients with inflammatory bowel disease.

in Acta Gastro-Enterologica Belgica (2009)

Mucosal Gene Expression of Antimicrobial Peptides in Inflammatory Bowel Disease Before and After First Infliximab Treatment

in PLoS ONE (2009), 4(11), 7984

Background: Antimicrobial peptides (AMPs) protect the host intestinal mucosa against microorganisms. Abnormal expression of defensins was shown in inflammatory bowel disease (IBD), but it is not clear ... [more ▼]

Background: Antimicrobial peptides (AMPs) protect the host intestinal mucosa against microorganisms. Abnormal expression of defensins was shown in inflammatory bowel disease (IBD), but it is not clear whether this is a primary defect. We investigated the impact of anti-inflammatory therapy with infliximab on the mucosal gene expression of AMPs in IBD. Methodology/Principal Findings: Mucosal gene expression of 81 AMPs was assessed in 61 IBD patients before and 4-6 weeks after their first infliximab infusion and in 12 control patients, using Affymetrix arrays. Quantitative real-time reverse-transcription PCR and immunohistochemistry were used to confirm microarray data. The dysregulation of many AMPs in colonic IBD in comparison with control colons was widely restored by infliximab therapy, and only DEFB1 expression remained significantly decreased after therapy in the colonic mucosa of IBD responders to infliximab. In ileal Crohn's disease (CD), expression of two neuropeptides with antimicrobial activity, PYY and CHGB, was significantly decreased before therapy compared to control ileums, and ileal PYY expression remained significantly decreased after therapy in CD responders. Expression of the downregulated AMPs before and after treatment (DEFB1 and PYY) correlated with villin 1 expression, a gut epithelial cell marker, indicating that the decrease is a consequence of epithelial damage. Conclusions/Significance: Our study shows that the dysregulation of AMPs in IBD mucosa is the consequence of inflammation, but may be responsible for perpetuation of inflammation due to ineffective clearance of microorganisms. [less ▲]

Gene expression of antimicrobial peptides in colonic mucosa of patients with inflammatory bowel disease before and after first infliximab treatment.

in Gut (2008), 57(Suppl II), 102-103

Mucosal gene signatures to predict response to infliximab in patients with inflammatory bowel disease

in Journal of Crohn’s and Colitis [=JCC] (2008), 2(1), 64

Effect of infliximab treatment on colonic mucosal gene expression profiles in patients with inflammatory bowel disease

in Gut (2008), 57(Suppl II), 39