Genetic variation in FcRn affects anti-TNF drug concentrations

Last Updated: 2016-09-14

By Will Boggs MD

NEW YORK (Reuters Health) - A tandem repeat polymorphism in the neonatal Fc-receptor (FcRn) which extends the half-life of IgG influences anti-tumor necrosis factor (TNF) concentrations in patients with inflammatory bowel disease, researchers from Belgium report.

"We therefore feel genotyping for this FcRn tandem repeat should become part of the investigations physicians should do when starting a patient on a biological therapy," Dr. Severine Vermeire from Universitair ziekenhuis Leuven told Reuters Health by email. "As we have learned over the years that high CRP, low albumin, low BMI, all affect the pharmacokinetics of anti-TNF therapy (and hence also the efficacy or the pharmacodynamics of the drug), this factor now adds to this list of risk factors."

"Identifying risk factors in patients is important, as higher induction doses may be needed to ensure optimal disease outcome," Dr. Vermeire added.

Genetic polymorphisms result in the occurrence of a variable number of tandem repeats (VNTR) in the promoter region of the gene encoding FcRn. Monocytes from patients homozygous for 3 repetitions of this VNTR (VNTR3/VNTR3) express 66% more FcRn transcript and have increased binding to polyvalent IgG, compared with monocytes from patients heterozygous for 2 and 3 repetitions (VNTR2/VNTR3).

Dr. Vermeire's team investigated whether these polymorphisms influenced anti-TNF concentrations in a retrospective study of patients with inflammatory bowel disease, including 395 treated with infliximab and 139 treated with adalimumab.

The VNTR genotype was significantly associated with infliximab exposure only after excluding patients who developed antibodies to infliximab. VNTR2/VNTR3 patients had 14% lower infliximab drug exposure than homozygous VNTR3 patients, according to the August 2nd online report in The American Journal of Gastroenterology.

Among patients treated with adalimumab, the VNTR2/VNTR3 genotype was associated with 24% lower adalimumab exposure, compared with the VNTR3/VNTR3 genotype.

Male gender, VNTR2/VNTR3 genotype, elevated CRP, and hypoalbuminemia were risk factors for lower concentrations of both infliximab and adalimumab. Additional risk factors for lower concentrations of infliximab included ulcerative colitis diagnosis, prior non-infliximab anti-TNF use, and underweight, whereas additional risk factors for lower concentrations of adalimumab included prior infliximab use and overweight.

Infliximab and adalimumab exposure during induction therapy decreased with increasing numbers of risk factors.

"Physicians should be aware that the response to biological agents (regardless their class or mode of action) is variable between patients and that sufficient drug exposure during induction is of outmost importance to result in good outcomes (clinical remission and healing)," Dr. Vermeire said.

"Physicians should therefore use available tools, such as therapeutic drug monitoring, to measure and adapt doses to the individual patient," she added, "but what we now need are integrated predictive tools taking into account risk factors as prescribed above and who not only measure but also predict the doses necessary for patient x or y."

SOURCE: http://go.nature.com/2cd5ZPf

Am J Gastroenterol 2016.