Tissue TNF levels may exceed anti-TNF levels in patients with active IBD despite treatment

Last Updated: 2015-02-23

By Will Boggs MD

NEW YORK (Reuters Health) - In patients with active inflammatory bowel disease (IBD), tissue TNF levels that exceed anti-TNF levels may account for inadequate treatment responses, researchers report.

Several studies have shown correlations between serum anti-TNF levels and clinical outcomes, but none have evaluated intestinal tissue drug levels and their correlation with serum correlations and disease activity.

Dr. Maria T. Abreu from the Miller School of Medicine at the University of Miami, Florida, and colleagues in the ATLAS study sought to determine whether infliximab and adalimumab concentrations in intestinal biopsies were related to their serum concentrations and whether there was a relationship between tissue anti-TNF levels and systemic and mucosal inflammation.

The cross-sectional study included 24 patients with Crohn's disease and six with ulcerative colitis; 12 patients were receiving maintenance treatment with infliximab and 18 with adalimumab.

Serum and tissue drug levels correlated significantly for infliximab but not for adalimumab, the researchers report in Gut, online February 10.

Moreover, there was a significant correlation between serum anti-TNF levels and uninflamed-tissue levels that was not present for tissue samples with evidence of inflammation.

Within tissue specimens, there was a positive correlation between mild to moderate mucosal inflammation grades and TNF levels and between mild to moderate mucosal inflammation grades and anti-TNF levels. With more severe inflammation, however, tissue levels of anti-TNF were lower.

In patients with active inflammation, the ratio of anti-TNF in tissue to local TNF levels appeared to be decreased, resulting in lower levels of tissue anti-TNF despite elevated levels of serum anti-TNF.

Neither C-reactive protein nor serum TNF levels were useful for identifying patients with mucosal inflammation.

"Importantly," the researchers note, "in moderately to severely inflamed tissue, the anti-TNF to TNF ratio was lower, implying that there was insufficient anti-TNF to neutralize the TNF."

"While a 'therapeutic tissue drug level' is not defined, we postulate that the drug-to-TNF ratio in tissue may be more important than the drug level itself," they conclude. "Larger, prospective studies should address whether TNF levels, either in serum or tissue, can help predict dosing of anti-TNFs in an individual patient."

Dr. Asher Kornbluth from David Geffen School of Medicine at the University of California, Los Angeles, recently reviewed anti-TNF levels and outcomes in IBD.

"Our recently developed concept that serum infliximab levels are a good correlate of clinical response, now has to be interpreted in light of what is occurring on the tissue level, especially in inflamed mucosa," Dr. Kornbluth, who was not involved in the study, told Reuters Health by email.

"We are still learning how to interpret serum anti-TNF drug levels," he explained. "Rather than aim for a predetermined 'therapeutic range' we should consider that non-responding patients might benefit from pushing for higher levels. However, this hypothesis must be subjected to additional study before adopting this in clinical practice."

"Validation of assays of TNF levels in serum and tissue, and of tissue anti-TNF levels, might allow us to move towards an exciting new frontier in understanding the mechanisms underlying patient non-response and loss of response," Dr. Kornbluth said. "For now, there are no commercially available assays to measure serum TNF, or either TNF or anti-TNF levels in the tissue. We may therefore be left to guess whether a given patient may benefit from increased serum anti-TNF levels, even in the presence of a 'therapeutic anti-TNF drug level.'"

Prometheus Laboratories, which assayed the serum and tissue TNF and anti-TNF levels, employed four of the 10 authors of the new report.

Dr. Abreu did not respond to a request for comments.

SOURCE: http://bit.ly/1BGFauB

Gut 2015.