MAUI, HAWAII – Gastroenterologists are starting to embrace proactive therapeutic drug monitoring for inflammatory bowel disease patients on tumor necrosis factor inhibitors, according to reports at the Gastroenterology Updates, IBD, and Liver Disease conference.
M. Alexander Otto/MDedge News
Dr. Adam Cheifetz
Proactive therapeutic drug monitoring (TDM) is an alternative to standard combination therapy for inflammatory bowel disease, which involves giving a tumor necrosis factor inhibitor (TNFi) with an immunomodulator, usually azathioprine.
The immunomodulator is meant to prevent antibodies from forming against the TNFi and short-circuiting its effect. Growing evidence suggests that proactive TDM can do the same thing without the second drug and its sometimes fatal adverse events.
Serum TNFi levels are checked during induction, when the risk of antibody formation is highest if levels are too low, and increased upward if they are. Levels are also checked to make sure they aren’t too high, and sometimes followed during maintenance, speakers said at the meeting.
Commercially available serum assays make it easy; the turnaround time is a few days.
Reactive testing is too late
Reactive, instead of proactive, TNFi level testing is standard at the moment, which means levels are checked when people stop responding, but by then it’s often too late. “Why wait until a patient isn’t doing well and potentially has antibodies you can’t overcome before optimizing them? Why not deal with dose optimizing [tumor necrosis factor inhibitors] as opposed to using another drug like a thiopurine? This is common sense,” said gastroenterologist Adam Cheifetz, MD, director of the Center for Inflammatory Bowel Disease at Beth Israel Deaconess Medical Center and professor of medicine at Harvard Medical School, Boston, and a long-time advocate for proactive TDM.
Not too long ago, Edward Loftus, MD, a professor and consultant in the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., doubted the approach, but he’s since come around “now that we are starting to see higher level data.” In his own practice, he said he now checks infliximab levels at week 14, before the fourth infusion. Other clinicians check at week 6 before the third infusion.
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Dr. Edward Loftus
Whatever the timing, “If we are going to put somebody into remission, it’s going to be in that first 3-month window, so I think early optimization is important. Once you’ve adjusted the dose and optimized it, it might be something you want to check once a year. In my own practice, I’ve been inclined to do more combination therapy, but we’ll see how this goes,” Dr. Loftus said.
The evidence
Both presenters reviewed a recent randomized trial from Israel in pediatric Crohn’s patients induced with adalimumab. Trough levels were checked and adjusted as necessary to concentrations of 5 mcg/mL at weeks 4 and 8, and every 8 weeks thereafter, in 38 children; 40 others were randomized to reactive monitoring, with adjustments to the same trough level. Most of the children in the proactive group had dose intensifications, versus fewer than two-thirds in the reactive group.
At week 72, 31 children (82%) in the proactive group, but only 19 children (48%) in the reactive group, met the study’s primary endpoint, sustained corticosteroid-free clinical remission at all visits (Gastroenterology. 2019 Oct;157[4]:985-96.e2).
In short, “proactive TDM was far superior to reactive testing,” Dr. Cheifetz said.
There’s a question if the results would translate to adults, but, Dr. Loftus said, they beg “the issue of if I should be checking adalimumab trough levels at weeks 4 and 8. It certainly gives you pause to think about doing that.”
Among other reports, Dr. Cheifetz also reviewed a retrospective study of 264 patients – almost two-thirds with Crohn’s disease, the rest with ulcerative colitis - on infliximab maintenance therapy; half had proactive TDM, and the rest reactive monitoring. The target trough concentration was 5-10 mcg/mL; median follow-up was 2.4 years. He was the senior investigator.
On multiple Cox regression analysis, the proactive group had an 84% lower risk of treatment failure, an 84% lower risk of IBD hospitalization, a 75% lower risk of antibody formation, an 83% lower risk of serious infusion reactions, and a 70% lower risk of IBD surgery (Clin Gastroenterol Hepatol. 2017 Oct;15[10]:1580-8.e3).
Dr. Cheifetz said he uses assays from Prometheus Laboratories for proactive TDM, but there are other options. Prometheus turnaround times are a few days. He and his colleagues also have a website – www.bridgeibd.com – where doctors can plug in patient characteristics and get proactive TDM advice.
Dr. Cheifetz is a consultant for Prometheus, as well as Janssen, Abbvie and other companies. He disclosed research funding form Inform Diagnostics. Dr. Loftus is a consultant and/or has research funding from Abbott, Pfizer, and other companies.