Tauseef Ali, MD, on Biomarkers for the Optimization of IBD: Finding Precision

Dr Ali discusses his presentation from the Advances in Inflammatory Bowel Diseases virtual regional meeting on June 19 on using biomarkers to ensure optimal outcomes for patients with IBD.

Tauseef Ali, MD, is an assistant clinical professor at the University of Oklahoma and gastroenterologist with SSM Health in Oklahoma City, Oklahoma.

TRANSCRIPT:

Dr. Tauseef Ali:  Hello. My name is Dr. Tauseef Ali. I'm Staff Physician at SSM Health and Clinical Assistant Professor at University of Oklahoma. On June 19th, I presented a talk on AIBD Regionals on a topic of biomarkers for the optimization of IBD finding precision. It was a very interesting talk. I will share some key points with you tonight.

As we know, the management of IBD has evolved into a concept of treat-to-target. In this concept, we have a tight control of our patients through therapeutic drug monitoring, optimizing our drug therapy so that we can have a better disease control and control of inflammation for a better outcome.

We need biomarkers to have an optimization of care. The challenge of biomarkers in IBD include accuracy, predictive value, and the fact that IBD is a very heterogeneous disease.

What we really want is the identification of biomarkers that can help us, our IBD patient population, to get categorized into high risk vs low risk patient, so that our high-risk patient can get top-down therapy, aggressive therapy so we can prevent complications, and our low-risk patients may be needing to get started on a step-up therapy so that we can minimize the toxicity or side effects of the therapy and can still have better outcomes.

When it comes to biomarkers, the way I presented my talk, I categorized biomarkers into 3 major categories — prognostic biomarkers, which predict the disease scores;, predictive biomarkers, which predict the treatment response; and monitoring biomarkers, which monitor the treatment response.

In terms of predictive markers, we discussed certain genetic signatures that can actually help predict which patients will develop penetrating disease and which patients will develop stricturing disease. For example, genes that regulate extracellular matrix accumulation were present in patients who subsequently developed strictures. The same study showed that genes that regulate the acute inflammatory response to microbes, they were present in patients who subsequently developed penetrating disease.

We also looked at the studies where gene expression profiling of CD8 plus T cells. With that expression profiling, we were able to categorize our patient into high-risk and low-risk patients. We discovered that high-risk patients were the ones who actually ended up having more treatment escalation compared to the patients who were low risk.

That has also led development of Web-based prediction tool. It's to personalize the risk assessment. You can input different values including the disease location, serological markers, data from genetic mutations. Then you can calculate a person's risk of complications for the next 3 years. I'm really hopeful that this predictive tool is used in clinical practice in very near future.

In terms of predictive biomarkers to predict the disease response, we reviewed the data for TPMT and NUDT15 to predict the thiopurine-related hematotoxicity that patients who have the mutations in these genes can develop leukopenia. That is very well-known fact to us. We also looked at the recent data showing that there are certain genes that can predict response to infliximab therapy both in ulcerative colitis and Crohn's disease.

Most recently, in 2020, the study that showed the HLA-DQA1*05, that's an allele, the mutation in that gene actually is present in about 40% of the Europeans. It has been shown now that it increases the rate of immunogenicity. Someone that carries that gene mutation on HLA-DQA1*05 actually are at higher risk of developing antibodies to biologic therapies such as infliximab and adalimumab.

We also reviewed data in terms of genetic predictors in vedolizumab or etrolizumab. We discovered that there is an integral alpha-E gene expression. When that gene expression is higher, response is better actually or mucosal healing rate is even better.

Last category was the monitoring biomarkers. How do you monitor the disease? We are all well aware of fecal calprotectin, how fecal calprotectin is predictive of increased inflammation, and a very good biomarker that, nowadays, we are all using in our clinical practices.

What we learned during this meeting was that, in about 50% to 80% of patients who actually stopped showing an upward trend, we know that even before they have a flare, we can actually predict a disease relapse within the next 2 to 3 months if they are showing an elevated calprotectin.

Patients who have sustained normal calprotectin level, we can predict in about 60% to 90% probability that they will remain in remission in the next 2 to 3 months. Not only we have fecal calprotectin, we have fecal immunochemical test, FIT test, that has also been shown to be helpful. We have radiologic biomarkers. We can layer the terminal ileum thickness that can predict the treatment outcomes such as patients who have a small bowel thickness of more than four millimeter. They are associated with higher risk of treatment failure.

How do we put all these biomarkers in clinical practice? I shared with them our well-known CALM clinical trial that was published in 2018 that showed that when you use biomarkers, compared to clinical management, you get better outcomes.

Similarly, now in 2021, this year, we have our STRIDE-II recommendations or consensus guidelines that does incorporate normalization of CRP as one of our desired short-term goals, decrease in calprotectin, perhaps an intermediate goal, and endoscopic healing as one of our preferred long-term goals.

There is a fascinating evolution of precision medicine in IBD. Right now, we have some existing biomarkers such as CRP, fecal calprotectin, TPMT. We layer drug levels, antibodies. Then we have some potential biomarkers, genomic markers, epigenomic markers, microbiomes that we are using that will all help us stratify and predict the risk of complications, disease activity, side effects of the medications, prognosis. That can help us individualize care of these patients and, perhaps one day, will help us lead to finding a cure for these patients.

Lastly, I presented 2 major trials that are ongoing. It's glimpse into the future of precision medicine in IBD. We looked at the PROFILE trial, where patients are being stratified based on biomarkers. We will be seeing the outcomes in these patients.

There is another trial, the PRECIOUS study, which is predicting Crohn's and colitis outcomes in the United States using a prognostic biomarker. We are looking forward to the results of these two studies.

Putting it all together, what I shared with my colleagues on that day was how we can use predictive markers, diagnostic markers, and then therapeutic markers, safety markers, monitoring markers, in the care of our IBD patient. There has been significant progress in recent years for developing biomarkers and incorporating them in our clinical practice.

Still, a substantial unmet need is present when it comes to biomarkers and stratifying patients and their treatments. It requires knowledge, tools, and infrastructure, that's very important, to perform this high-throughput analysis. I would say that high-quality biomarker-driven IBD care is the future that is not too far from us.

Thank you for listening. I hope I'll see you guys in our annual AIBD meeting in Orlando this year. Thank you.