Note from CCFA's National Scientific Advisory Committee:
This study found that there are potential genes associated with responses and non-responses to infliximab in patients with ulcerative colitis. The findings of this study are not ready for clinical use though as more studies are required to validate these findings in the general UC population.

Gene signature predicts infliximab response in ulcerative colitis

Last Updated: 2009-12-25 9:30:06 -0400 (Reuters Health)

NEW YORK (Reuters Health) - While the anti-tumor necrosis (TNF)-alpha agent infliximab - marketed by Centocor as Remicade -- is an effective treatment for ulcerative colitis, about 40% of patients do not respond to the drug. Predicting which patients will fail to respond has so far been impossible.

Now, however, researchers from the United States and Belgium have identified a mucosal gene signature that could do so, which could in turn improve safety and optimize the use of resources.

"Our studies demonstrate that a limited number of genes involved in the inflammatory cascade account for resistance of ulcerative colitis to respond to anti-TNF-alpha therapy," Dr. Paul Rutgeerts from University Hospital Gasthuisberg, Leuven, Belgium and colleagues write in the December issue of the journal Gut.

The researchers used microarray probes to compare pretreatment colonic mucosal expression profiles for infliximab responders and non-responders in two independent cohorts of patients receiving infliximab for the first time for refractory ulcerative colitis.

Cohort A comprised 24 patients (8 responders and 16 nonresponders) from the University Hospital Leuven, while cohort B comprised 22 patients (12 responders and 10 nonresponders) from the Active Ulcerative Colitis 1 (ACT1) study, a placebo-controlled trial of infliximab.

They classified responders as patients who achieved complete healing both endoscopically and histologically; all other patients were considered non-responders, although some showed clinical improvement or mucosal healing at a later time point, note the researchers.

In a comparative analysis, the researchers identified a total of 179 differentially expressed microarray probe sets in cohort A and 361 in cohort B, "with an overlap of 74 probe sets, representing 53 known genes, between both analyses," the investigators report.

"These common probe sets were all downregulated at baseline in responders compared to non-responders," they note.

Comparative analysis of both cohorts combined (20 responders and 26 nonresponders) yielded 212 differentially expressed probe sets. The top five from this analysis were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin-13 receptor alpha 2, and interleukin-11.

"These markers separated responders from non-responders with 95% sensitivity and 85% specificity," Dr. Rutgeerts and colleagues report.

"We think that the markers identified in this study are specific for anti-TNF therapy," the team notes. Moreover, the five genes identified encode for proteins involved in the adaptive immune response, inflammation and TNF pathways.

"We plan to develop a predictive diagnostic chip with these five genes and to further prospectively validate this gene signature in ulcerative colitis patient candidates for anti-TNF treatment. In this manner optimal use of resources could be achieved and safety improved."

Several of the study's authors are employees of Remicade marketer Centocor, and a number of others have received grant support, lecture fees, or consulting fees from the company.

Gut 2009;58:1612-1619.