Biomarkers Have a Clear Role in Managing Crohn’s Disease

Treating patients with Crohn’s disease (CD) successfully, and earlier, can substantially offset their risk for long-term disability and the need for eventual surgical intervention. However, monitoring whether that treatment is successfully achieving its goals traditionally relies on endoscopy and all of its inherent limitations. The possibility that serum and fecal biomarkers of disease activity might one day provide a less-invasive alternative means of tracking treatment response has gained momentum in clinical circles.

The American Gastroenterological Association (AGA) recently weighed in on this important topic when they published a clinical practice guideline on the role of biomarkers for the management of CD. This represents the work of a multidisciplinary expert panel, who conducted a systematic review of the latest literature and offered 11 conditional recommendations.

Medscape Medical News reached out to the guideline’s lead author Ashwin Ananthakrishnan, MD, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, to discuss the evolving role of biomarkers in managing CD and the guideline’s key recommendations for which patients to best apply them.

Ashwin Ananthakrishnan, MD

The Growing Case for Biomarkers in CD

Why did the AGA feel it was important to release this guideline now?

In the current management of inflammatory bowel disease, we have recognized the importance of a treat-to-target strategy for achieving the best patient outcomes. In addition, we recognized that because subjective symptoms correlate poorly with objective inflammation, it is important to rely on objective tools to understand the status of inflammation.

While traditionally objective assessment has relied on endoscopy, this guideline emphasizes that fecal and serum biomarkers can, in the right clinical scenario, be very important in assessing the status of inflammation in patients with CD. Some payers, for example, have historically labeled biomarkers “experimental.” These guidelines, in reviewing extensively the published data, provide scenarios and cutoffs for appropriate use of these biomarkers and suggest that they should be viewed as standard of care.

We felt this was timely given that these biomarkers are increasingly available now in the United States and are being used in the care of our patients. We wanted to both support their use but also provide context for their interpretation.

Speaking to the timely nature of these guidelines, do you believe we’ve reached a point where biomarkers can potentially replace endoscopy in CD?

The goal of biomarkers is not necessarily to replace endoscopy. It is to ensure that patients are being monitored adequately with the optimal test, which in some cases may be biomarkers and in other cases is endoscopy.

Studies have looked at biomarkers for the past two decades, but initially, they were experimental. With a wealth of data now comparing it to the ‘gold standard,’ which is endoscopic evaluation, we can now robustly say there are several situations where measurement of biomarkers may be sufficient to guide management, and one does not need to perform endoscopic assessment.

What are some of the overall insights about the viability of biomarkers in managing CD that the guidelines provide?

Conceptually, interpretation of the biomarkers also depends on the pretest probability of identifying endoscopically active disease, which is influenced by the severity of symptoms.

In the absence of symptoms, a normal biomarker (fecal calprotectin or serum C-reactive protein [CRP]) confidently confirms endoscopic remission with very low false negatives.

Similarly, in the presence of moderate to severe symptoms, an elevated biomarker strongly suggests endoscopically active disease and can be used to guide most treatment escalation decisions.

Where there is symptom-biomarker disconnect, or in those with mild symptoms, endoscopic, or perhaps radiologic, assessment is important to truly define the presence of active disease prior to major treatment decisions.

Before we delve into the specific recommendations, why might biomarkers be viable in certain stages/types of CD and not others?

We recognized that biomarkers are directly proportional to the burden of inflammation. Consequently, in small bowel disease where there may be only a short segment of involvement, the biomarkers may not be elevated to that degree and produce false negatives. Similarly, for very proximal disease (upper gastrointestinal, stomach, and esophagus), the biomarkers may not be as elevated in the stool.

We also focused on biomarkers to assess the presence of active inflammation. There may be additional role for biomarkers in predicting the development of scar tissue, recurrence, etc. That was not the focus of this guideline.

Highlights From the AGA Panel’s 11 Recommendations

You and your colleagues on the AGA expert panel formulated patient-centered clinical questions, which you then used to derive a formal set of recommendations.

You first asked whether, in patients with CD in symptomatic remission, interval biomarker-based monitoring is superior to symptom-based monitoring to improve long-term outcomes. What was your answer?

Yes, an interval biomarker-based monitoring strategy is superior to symptom-based monitoring strategy.

In patients with CD in symptomatic remission, at what fecal calprotectin, serum CRP, and endoscopic healing index cutoff can we accurately rule out active inflammation, obviating routine endoscopic assessment?

A fecal calprotectin

There were a pair of recommendations specific to patients with symptomatically active CD. First, is an evaluation strategy that combines biomarkers and symptoms superior in these patients to symptom-based evaluation for making treatment adjustments?

Yes, a strategy combining both is superior to relying on symptoms alone.

Then again in these patients with symptomatically active CD, at what biomarker cutoff levels can we accurately diagnose active inflammation and forgo the need for routine endoscopic assessment?

In patients with CD with mild symptoms, elevated biomarkers of inflammation (fecal calprotectin> 150 mcg/g, CRP> 5 mg/L) are insufficient to identify endoscopically active inflammation, and endoscopic assessment, or radiologic assessment, is suggested rather than empiric treatment adjustment. This recommendation also applied to those with normal biomarkers of inflammation.

In those with moderate to severe symptoms, elevated biomarkers reliably rule in inflammation and can be used to guide treatment adjustment. Normal biomarkers are not sufficient to rule out inflammation and should confirmed by endoscopic or radiologic assessment.

There was a similar question about patients with CD in surgically induced remission. What were the biomarker cutoffs in this cohort that you and your colleagues felt we can accurately rule out postoperative endoscopic recurrence, without the need for routine endoscopic assessment?

In those who are at a low risk for postoperative recurrence, a fecal calprotectin

In patients with established CD, is interval biomarker-based monitoring strategy superior to interval endoscopy-based monitoring strategy to improve long-term outcomes?

There is insufficient data to address this, so we did not make any recommendations.

In offering these recommendations, what immediate impact do you think they’ll have on the clinical practice of gastroenterologists treating patients with CD?

We envision that gastroenterologists will feel more comfortable routinely using these biomarkers in the management of CD. In the right scenario, they can take the place of endoscopic assessment. It is also important to understand which scenarios these biomarkers perform poorly and, thus, should be followed up by endoscopic assessment for confirmation.

We need more data on how biomarkers behave longitudinally and how and when they should be measured after starting new treatments, etc.

What do you see potentially changing in the next edition of the guidelines?

There are limited data on biomarkers other than CRP or fecal calprotectin. In the next edition, we may be able to comment on additional biomarkers. We may also be able to comment on serial measurement of biomarkers and how to use them in combination with other tests such as CT, MRI, and intestinal ultrasound.

Ananthakrishnan did not have any relevant disclosures.

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