Raymond Cross, MD, on Precision Medicine and Companion Diagnostics in IBD: Ready for Prime Time?

In this video, Raymond Cross, MD, discusses his session on precision medicine and companion diagnostics in IBD, which he presented at the virtual 2020 Advances in Inflammatory Bowel Disease (AIBD) regional meeting on July 25. 

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Raymond Cross, MD, is director of the Inflammatory Bowel Disease program at the University of Maryland Medical School in Baltimore, MD, and a co-chair of the virtual Advances in Inflammatory Bowel Disease 2020 regional meetings. 


Hi everyone, my name is Raymond Cross. I am a professor of medicine and director of the Inflammatory Bowel Disease Program at the University of Maryland School of Medicine. I'd like to give a brief synopsis of my talk presented at the Chicago advances in IBD course, which was entitled "Precision Medicine Companion Diagnostics ‑‑ Are They Ready for Primetime?"

When we think about precision medicine, the way I organized my talk was into three parts. As a provider seeing a patient with Crohn's or colitis for the first time, it's really important that you have some idea of whether that patient is going to have a more severe disease course or a milder disease course. You can think of this as prediction.

Unfortunately in 2020, we do not have great regularly used commercially‑available tests to predict a severe disease course for a patient. There are some antibodies to microbial antigens which have been shown to correlate with complicated disease, small bowel disease, and the need for surgery.

There are some genetic mutations associated with surgery and need for recurrent surgery. In general, we don't have good tools yet to predict who's going to have the most severe disease course. Those patients, of course, would be selected for earlier and more aggressive biologic therapy.

As far as thinking about a patient who's already had an operation, there are some noninvasive biomarkers that are pretty good at predicting recurrent disease. We've had to utilize these tests in the COVID pandemic because endoscopy has been more limited.

Fecal calprotectin can be a very good marker of recurrent disease and can help you re‑stratify what patient should have a colonoscopy versus what patient that can be deferred. We do have ongoing prospective cohorts in both pediatrics and adults where we are trying to identify predictors of severe disease.

One of those studies was recently published from the risk cohort funded by the Crohn's & Colitis Foundation showing that the highest quartiles of extracellular matrix one are associated with progression from an inflammatory destructuring phenotype. I think there's going to be more to come regarding prediction of severe disease but not ready for primetime.

The next topic area is identifying the right drug for the right patient at the right dose at the right time. We have some of those tools. Using thiopurine as an example, checking a thiopurine methyltransferase activity before starting therapy can help us identify whether we do a full‑dose or three‑quarter dose, or we don't give the drug at all because it's not safe. That's a classic example.

With anti‑TNFs, we have some idea of what levels are needed to achieve a clinical response and to achieve mucosal healing. We don't have good algorithms to start out at the right dose at the right interval, although Marla Dubinsky from Mount Sinai has preliminarily shown you can predict drug levels and likewise what dosing would be needed. We talked about some of those thresholds in my talk.

Lastly, this is particularly relevant during the COVID pandemic: We're now in this treat to target world. Why do we need treat to target? Clearly, we know that a significant number of patients with Crohn's and colitis, particularly Crohn's, can have a disconnect between their symptoms and what's going on from an inflammatory perspective within their intestinal tract.

For example, some patients can be horribly symptomatic, and they don't have any inflammation. This can be patients who have concurrent anxiety and depression, those who have chronic pain, functional overlap, those that have been surgically altered in the past. In those patients, they're at risk for overtreatment based on symptoms.

There's another subgroup of patients that don't have any sensors for their inflammation, and they're relatively asymptomatic until they present with a complication.

Now, when we initiate treatment, we first verify that disease is present. Three to 6 months after initiating an optimizing therapy, we then do a repeat assessment to verify that there's been at least significant improvement. If not, complete healing of the endoscopic inflammation.

In COVID, that was extremely difficult to do due to the limited ability to do endoscopy. We had to rely more on some of our non‑invasive biomarkers. An example is CRP which, unfortunately, is not helpful in 15 to 30 percent of patients. CRP also can be raised by other conditions. For example, obese patients may have an elevated CRP.

The most commonly used noninvasive biomarker other than CRP is fecal calprotectin. We go over the evidence for using calprotectin as a marker of intestinal inflammation, which is actually quite good—not perfect, but quite good.

We talk about some of the newer biomarkers, the CD monitor test, which is newly developed. It has 13 different biomarkers that are used in combination and showing that in a bio-naive population that test is quite accurate, and at least as good as a fecal calprotectin. For patients that are averse to giving you a stool sample, that can be one thing that we can use.

I don't think, as gastroenterologist, that we're going to move away from doing repeat procedures after changing therapy. Some of these companion diagnostics maybe can be used as an early look to get a sense of things to moving in the right direction.

If we're in a lockdown situation again, we're going to have to replace unfortunately our standard endoscopy. I would anticipate that over the next 10 to 20 years, we're going to get even better biomarkers that are going to assess inflammation.

That's a brief summary of my talk. Hopefully, you enjoyed it. Thank you very much for listening.