Biomarkers for the Optimization of IBD: Finding Precision

In his presentation at the Advances in Inflammatory Bowel Diseases virtual regional meeting April 16, Dermot McGovern, MD, said, “We are already practicing precision medicine” in providing care for patients with inflammatory bowel diseases (IBD), but that gastroenterology still lacks the ideal biomarkers to help better predict which patients are most likely to respond to certain therapeutics and which are at higher risk for complicated disease in the future.

Dermot McGovern, MD, is director of Translational Medicine at the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute at Cedars-Sinai in Los Angeles, California.

Dr McGovern began by noting that ideal biomarkers should be accurate, reproducible, easy to implement, minimally invasive, readily available, affordable, fast, with good sensitivity and specificity, and provide clinically useful information.

“We essentially don’t have these in IBD,” he said. “If anyone knows of one, please let me know.”

IBD is a very complex disease, Dr McGovern said, in which “genetics, microbiota, the immunome, and the environment all add to the complexity. We need to understand how these all intersect to create chronic gut inflammation.” In addition, IBD is very heterogenous, he stated, with different ages of onset and complexity of disease, extraintestinal manifestations, and differing response rates to therapies.

“The IBD pipeline is potentially very rich, not just for monotherapy but also in combinations of therapeutics,” he added. “The goal is to figure out how we bring all this together to get the right drug to the right patient at the right time, which is what we all want.”

Dr McGovern said, “We all know some of the clinical biomarkers that identify people who are more likely to have complicated disease—such as strictures, young age at onset, perianal disease, and smoking in Crohn disease, and in ulcerative colitis, colectomy, and young age of onset, among others. So we are already practicing precision medicine. But what can we do to improve our clinical practice?”

In the area of diagnostics, he noted that the mapping of the human genome held out hope of finding causative genes for IBD. While that has not happened, there has been progress in identifying individuals with monogenic IBD. A study conducted in Toronto found that 20% of pediatric patients with very-early-onset IBD have monogenic IBD. “Here you have a causative gene,” he said.

Serological markers have been used for some time and can provide important information about which patients are at risk of developing more complex disease and to require surgery, he said. Dr McGovern referenced previous studies in which patients in clinical remission from Crohn disease were found to have elevated levels of C-reactive protein (CRP)—an indication that these patients are more likely to require hospitalization in the future.

“Clinical symptoms don’t always match what’s going on at the mucosal level,” he noted, adding,  “lots of us have realized that and incorporate that into our practice.” Markers that help to identify mucosal surface activity such as CRP, stool lactoferrin, and fecal calprotectin can be useful in practice, but that depends on pretest probability, he explained.

Patients with high levels of eosinophilia have also been found more likely to develop complicated disease and need hospitalization, and to experience a lower quality of life. “These tests are already in our clinic and readily available,” Dr McGovern said.

CRP and fecal calprotectin have been shown to predict clinical relapse. “Ee know these things become abnormal ahead of relapse,” he stated, noting that a subanalysis of the STORI trial showed that CRP elevation led clinical relapse by a few months. “A CRP of 6.1 mg/dL and fecal calprotectin of 305 mcg/g are the good predictors for relapse.”

Dr McGovern added, “A recent study concluded that prognostic markers need to be validated in large independent studies, and this is something that I think we all need to take on board.”

Genetics is providing valuable insight in how certain subsets of patients may respond to therapy or experience adverse effects, he commented. For example, a Korean study found that the NUDT15 genetic variant ““is a much bigger contribution to thiopurine-induced leukopenia in Korean populations than TPMT [thiopurine methyltransferase].” Similar results have been seen in Japan and China, as well.

“You have to understand the patient in front of you,” Dr McGovern stressed, commenting that with a patient of Asian-American descent this information can be extremely important in helping avoid thiopurine-induced leukopenia.

An association with immunogenicity to infliximab and adalimumab has also been found in patients with an HLA-DQAI*05 allele, he noted. “If you carry one of these alleles and are on infliximab monotherapy, the risk of immunogenicity is 90% within a year. However, in a patient a thiopurine or methotrexate, the risk drops to 20%.”

Dr McGovern noted that genetics tests are increasingly available, and that “the cost of profiling a genome has dramatically dropped, in contrast to run ordinary lab results; if you look a someone’s genome, actional variants exist in 60% of IBD patients; that data is always available and doesn’t change.”

He stressed, “This is an evolution, not a revolution. We do work in the space of precision IBD now but you need to personalize your precision approach and understand how these biomarkers behave in your patient. This is precision medicine you’re personalizing for the patient in front of you.”

McGovern D. Biomarkers for the Optimization of IBD: Finding Precision. Talk presented at: Advances in Inflammatory Bowel Diseases regional meeting. April 16, 2021. Virtual.