Genetics may help predict response to anti-TNF therapy in Crohn's

Last Updated: 2016-09-15

By Megan Brooks

NEW YORK (Reuters Health) - Researchers have identified genetic risk markers that could help predict non-response and durable response to anti-tumor necrosis factor (anti-TNF) biologic therapy in patients with Crohn's disease.

One in five patients with CD do not respond to anti-TNF therapy, and up to 15% will lose response to therapy each year. Why this is so remains unclear, as does the role of genetics in non-response and lose of response, according to Dr. Ashwin Ananthakrishnan and colleagues from Massachusetts General Hospital and Harvard Medical School in Boston.

The researchers set out to identify genetic factors associated with primary non-response and loss of response to anti-TNFs in CD. They studied 359 patients from the Prospective Registry in IBD Study at Massachusetts General Hospital (PRISM). All had a diagnosis of CD based on standard criteria; had received anti-TNF therapy with infliximab, adalimumab or certolizumab pegol; and had genotyping performed on the Illumina Immunochip.

Thirty-six patients (10%) had primary non-response (PNR) to anti-TNF therapy. These patients were more likely to have had longer disease duration before starting therapy (15 vs. 10 years), were older at diagnosis (29 vs. 25 years), and were more apt to smoke (53% vs. 33%). Isolated colonic involvement was also more common among PNR patients (42% vs. 22% for responders).

Genetic analysis revealed 15 risk alleles associated with PNR and were incorporated into a genetic risk score (GRS).

Primary non-responders had a significantly higher GRS than patients without PNR (16.4 vs. 11.2). On multivariable analysis including relevant clinical factors, the PNR GRS was the only significant independent predictor of PNR (odds ratio, 2.65), the researchers report.

A model combining genetic and clinical variables more accurately predicted PNR compared with a clinical only model (AUROC 0.93 vs. 0.70, p<0.0001).

Genetic analysis also revealed 16 single nucleotide polymorphisms that predicted durable response to anti-TNF therapy. Patients achieving durable response had a significantly higher GRS than those who did not (15.0 vs. 11.2).

On multivariable analysis, only the GRS and no prior resection were independently predictive of durable response. Each 1-point increase in the GRS was associated with a 60% increase in likelihood of durable response.

The separate GRSs for PNR and durable response were not mutually correlated, "suggesting distinct mechanisms," the researchers note in their report, online September 6 in the American Journal of Gastroenterology.

Summing up, the researchers say, "Given the significant likelihood of primary or secondary non- response to anti-TNF agents and with growing availability of therapies targeting CD through diverse pathways, there is an important unmet need to define predictors and mechanisms of response to each therapeutic class."

The significant improvement in predictive value with genetics, particularly for PNR, "offers the potential to tailor therapy to individuals based a priori on likelihood of response. This allows us to accurately balance risks of therapy with likelihood of benefit. In addition, with growing availability of therapies with distinct mechanisms of action, this approach allows for potentially matching the patient to the drug," they add.

"The next step," Dr. Ananthakrishnan told Reuters Health, "would be a replication study in an independent population. Subsequent steps would be to see if the risk score is specific to anti-TNF response and if other risk scores may be valid for other therapeutic mechanisms such as anti-integrin therapy."

"Once that information is available, one can hope that genetics may be helpful in informing comparative effectiveness (and safety) of different therapies in a given patient, and thereby facilitating a more informed and personalized therapeutic algorithm," Dr. Ananthakrishnan said by email.

"These findings are very noteworthy," Dr. Eugene Yen, Clinical Director of the Center for Crohn's and Colitis at NorthShore University HealthSystem in Illinois, who wasn't involved in the study, told Reuters Health.

"The impact that genetic factors might have on anti-TNF therapy in Crohn's disease has been in discussion for many years, and it is exciting that there is emerging research on this. While the results are preliminary, this is one of the first steps towards personalizing therapeutic decisions for our patients with inflammatory bowel disease," Dr. Yen said by email.

He thinks the findings could eventually influence clinical practice. "As a clinician, if we knew in advance who would not respond to these therapies, we are much more likely to recommend a different course of therapy, as we now have other biologic agents, as well as clinical trials, looking at other mechanisms for treatment in patients with Crohn's disease," Dr. Yen said.

"If the research progresses and there are genetic markers that can more accurately quantify the likelihood of response to certain medications, I do see genetic testing eventually playing a much larger role in the care of our patients with Crohn's disease," he added.

The study had no commercial support. Dr. Ananthakrishnan has disclosed relationships with Cubist Pharmaceuticals, Abbvie, Exact Sciences and Amgen.

SOURCE: http://go.nature.com/2cxNDpJ

Am J Gastroenterol 2016.