Is Precision Medicine for IBD Ready for Prime Time?

Precision medicine is developing in the diagnosis and treatment of inflammatory bowel disease (IBD), as genetic testing and assessment of prognostic factors are being used to guide treatment decisions and monitoring, explained Millie Long, MD, at the August 22 virtual Advances in Inflammatory Bowel Disease regional meeting.

Dr Long is vice chief for education and associate professor of medicine at the Inflammatory Bowel Disease Center at the University of North Carolina at Chapel Hill.

She noted that precision medicine is defined as “medical care designed to optimize efficiency or therapeutic benefit to particular patients, especially using genetic or molecular profiling.” One of the latest advances in IBD is the use of genetic testing to determine whether a patient carries the human leukocyte antigen (HLA) DQA1*05, which appears to predict immunogenicity to anti-tumor necrosis factor (TNF) therapeutics in patients with Crohn disease who are biologic naïve.

“Patients with this gene who start treatment on anti-TNF monotherapy develop immunogenicity very quickly,” Dr Long explained. “So, they really need combination therapy with an immunomodulator. If there is a contraindication to immunomodulators in these patients, then don’t start their treatment with a TNF inhibitor; choose another therapeutic agent.”

She noted that data from clinical trials of various therapeutic agents used for treating IBD make it clear that these “are not overwhelmingly effective.” The VARSITY trial of treatment for ulcerative colitis showed, for example, that at week 52, clinical remission was maintained overall in 22.5% to 31.3% of participants in a head-to-head trial of adalimumab vs vedolizumab, respectively. Therefore, Dr Long stressed, “we have to optimize these agents and position them appropriately to give our patients the best chance at achieving and maintaining remission, while also accounting for risks.”  

She reviewed the case of a 23-year-old woman with significant weight loss, frequent bowel movements, and rectal bleeding with most stools. Dr Long stated that she proceeded quickly with a colonoscopy that yielded a Mayo 3 ulcerative colitis score.

Whereas previously the disease severity would have been determined entirely according to symptoms, “now we consider context and especially prognostic factors. We now emphasize the role of endoscopic scoring and look at inflammatory markers such as fecal calprotectin and C-reactive protein.”

The importance of prognostic factors was clear in this case, Dr Long said. The diagnosis prior to age 40 years, the severity of endoscopic, and extensive colitis are all poor prognostic indicators. Treatment goals set by the STRIDE guide now advise setting a goal with composite endpoints of clinical remission, based patient-reported outcomes, and endoscopic remission, frequently reassessed.

When positioning therapies for patients with IBD, Dr Long said, “You need to look at the subpopulations—patients [older than] 65 years, those who are already inpatients due to their IBD, patients with a significant history of cancer, those with extraintestinal manifestations (EIM), and anti-TNF failure.”

She stated that for patients who have been exposed to anti-TNF therapeutics, the best options to date are ustekinumab and tofacitinib. For patients with low albumin, she noted, “Treating these patients with anti-TNFs could be a waste, while cyclosporine can induce remission.”

Symptoms often do not correlate with inflammation, Dr Long stated, which is why the American College of Gastroenterology now sets mucosal healing as a goal of therapy. Endoscopic scores should be monitored carefully due to this lack of correlation; patients in clinical remission may still show inflammation and endoscopic activity. She advised evaluation within 1 year of resection for postoperative endoscopic recurrence to guide therapy in patients who have undergone this procedure.

The lack of comparative effectiveness data between therapeutic agents complicates positioning, Dr Long stated, though some meta analyses have provided helpful information.

In summary, Dr Long advised that moderate to severe IBD should be defined through disease severity, not disease activity. Gastroenterologists need to understand positioning of therapies, based on individual factors such as age, comorbidities, EIMs, and other prognostic factors, and the relationship between therapeutic efficacy and safety.

“When using anti-TNFs, combination therapy with thiopurine is most effective,” she said, noting again that testing for HLA DQA1*05 may predict immunogenicity to anti-TNF medications in patients with Crohn disease. For outpatients with moderate to severe ulcerative colitis, Dr Long suggested the use of vedolizumab over adalimumab.

For the present, Dr Long said, it is vital to understand the risk factors for a complicated course of disease in both ulcerative colitis and Crohn disease in order to effectively personalize therapy.

—Rebecca Mashaw

Reference:

Long MD. Precision Medicine: Ready for Prime Time? Talk presented at: Advances in Inflammatory Bowel Disease 2020 regional meeting; August 22, 2020; virtual