July 12, 2022 | An international group of researchers has shown that a biomarker may help predict complicated Crohn’s disease and can be detected long before diagnosis.
According to Arthur Mortha, an assistant professor of immunology at the University of Toronto, he and colleagues have identified a blood biomarker that is involved in the development of Crohn’s disease and shows up years before the condition winds up revealing its full clinical spectrum.
In a paper published in Gastroenterology (DOI: 10.1053/j.gastro.2022.05.029), Mortha and researchers from Portugal, France, and Mount Sinai in New York indicated that their findings could “open new roads” for the diagnosis, classification, and treatment of Crohn’s disease—a chronic condition of the intestine that can cause symptoms such as abdominal pain, anemia, diarrhea, and weight loss.
Currently, there is a lack of simple, effective biomarkers prior to diagnosis, noted a press release announcing the new findings. Some see promise in the possibility of a blood test that could provide a fast, inexpensive, and non-invasive method of evaluating risk for complicated Crohn’s disease. This could enable preventive measures before chronic symptoms set in.
Crohn’s disease is a potentially destructive illness that impacts millions of people across the globe, explained Elliot Coburn, a gastroenterologist at the Gastroenterology Associates of New Jersey who was not involved in the study.
“It is important to always try to stay one step ahead of the disease in an effort to prevent complications from arising,” he told Diagnostics World.
Coburn called the exploration of novel biomarkers, like the one examined in this recently published paper, an “exciting endeavor” because it offers new tools to help identify people who are at a higher risk of experiencing complicated disease courses.
“Having this information available will allow us to achieve earlier disease detection, monitor higher risk patients more closely, and initiate more effective treatment strategies to ensure better outcomes for our patients,” he added.
Biomarker Detected Up to 7 Years Before Diagnosis
Inflammatory bowel disease, which is sub-classified into Crohn’s disease and ulcerative colitis, is a chronic inflammatory pathology of the gastrointestinal tract.
The causes remain a bit of a mystery but are thought to involve various contributors, such as genetics and environmental factors. Identifying the factors that can help predict disease onset is “of high clinical relevance,” the researchers noted in their paper.
A cytokine called Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) maintains immune balance within the intestine. However, in ileal Crohn’s disease patients, anti–GM-CSF autoantibodies (aGMAb) block the function of GM-CSF.
In the literature, aGMAb has been recorded in patients diagnosed with a complicated form of Crohn’s disease, Mortha told Diagnostics World. But it wasn’t well understood how this particular biomarker actually works, so he and colleagues set out to learn more.
To arrive at their findings, the group used a biorepository operated by the U.S. Department of Defense. When soldiers are recruited, they undergo a routine checkup, explained Mortha, who is the lead author of the study. A blood sample is drawn, and those samples are stored.
Over the course of service, some of those soldiers go on to develop Crohn’s disease. This study collected samples over roughly a decade from 220 military personnel who eventually developed this illness. The researchers compared the samples to 200 patients with ulcerative colitis and 200 healthy controls.
“We were able to basically select those patients that develop Crohn’s disease and match healthy controls that were recruited during a similar period—and traveled back in time by analyzing blood samples that were collected before the disease was diagnosed,” Mortha said.
The recently published research revealed that in a subset of Crohn’s disease patients, these antibodies (aGMAb) neutralized the protective effects of the cytokine (GM-CSF) and disrupted intestinal equilibrium.
Over time, these changes weakened the immune system and damaged the lower portion of the small intestine, leading to a condition called complicated ileal Crohn’s disease. Notably, these changes were detectable long before diagnosis.
“We were surprised to see that this biomarker could be detected up to seven years before the disease was even diagnosed,” Mortha said. He called the discovery “absolutely amazing” because it offers new possibilities for disease interventions.
The biomarker was present in roughly a quarter of those who developed Crohn’s disease. Although it predicted risk for complicated ileal Crohn’s disease, not all those with the antibody displayed the same form or severity of disease, which highlights the multi-factorial nature of the illness.
The researchers noted that this line of work supports the growing interest in exploring the preclinical phase of Crohn’s disease, where prevention strategies could be pursued. The association of aGMAb with complicated Crohn’s disease may eventually help identify appropriate candidates for disease prevention at its earliest stages.
While Coburn noted that the findings from this study by Mortha and colleagues are intriguing, there are also some notable limitations to consider. He explained that “larger scale, multi-center, prospective studies” will probably be needed before implementation in clinical practice, for instance.
“Though impressively specific for the development of Crohn’s disease, the low sensitivity of positive aGMAb titers could limit its use as an effective screening test,” Coburn added.
Hyperactivity Versus Paralysis: Viewing Crohn’s Disease Differently
The road leading up to this recently published research all began with observations in mice, said Mortha, and the finding that innate lymphoid cells and T cells produce GM-CSF, an important protein for another group of important immune cells.
GM-CSF allows the receiving immune cells (including macrophages, dendritic cells, and neutrophils) to become better able to defend the host and its organs against bacterial infections, he explained.
These observations (DOI: 10.1016/j.chom.2010.01.006) revealed that animals deficient in GM-CSF are susceptible to infections by intestinal pathogens and demonstrate a far more severe disease outcome.
The immune system’s cells that mediate this tolerance against the gut’s natural microbes are also affected if GM-CSF is absent, a separate study found (DOI: 10.1126/science.1249288), which suggests that this immune protein is needed to maintain a healthy intestine.
This differs from other inflammatory conditions. In inflamed joints, for example, inflammation is less severe if GM-CSF is not present, Mortha noted, which is an aspect that has likely prevented many other researchers from investigating the role of GM-CSF in maintaining a healthy organ.
It goes against the way Crohn’s disease is currently viewed. Everybody tends to see it as an inflammatory disease, he explained, where the immune system is hyperactive. As a result, current treatments either prevent the accumulation of inflammatory immune cells in the intestine or target their inflammatory proteins.
“In some patients, this treatment works quite well,” Mortha said. “They go into remission as their disease improves significantly.” But the therapeutic options currently available for Crohn’s disease patients also have drawbacks. Some patients don’t respond well—an indicator that not every type of this Crohn’s disease is the same.
A biomarker or predictive indicators that could help guide interventions are a clinical need, according to Mortha, and his group’s characterization of aGMAb suggests that it is a feasible therapeutic target for intervention and perhaps even prevention.
The prior research conducted on animals suggested that the immune system is not hyperactive but instead “kind of paralyzed,” he said, left unable to defend or sustain a healthy intestine. And the biomarker found in Crohn’s disease patients essentially “mediates the paralysis of the immune system.”
He and colleagues wanted to explore this dynamic further in the hopes of finding greater heterogeneity in a disease that is complex and heterogeneous in nature but not necessarily viewed that way in clinical settings.
According to Mortha, the newly published research reveals “that there is a subset of patients that actually are not showing this classical hyper-activation of the immune system but rather a paralysis.”
It highlights the notion that there is more than one form of this disease that needs to be treated, and it is important to identify patients that demonstrate a unique form of illness. And because the biomarker is potentially detectable long before the disease is diagnosed, it enables the possibility of finding these patients prior to disease development.
“So you can actually think about a nice intervention for a subset of patients before they will develop the disease, which is currently not possible,” he added. “Nobody has done that in Crohn’s disease.”
Next Steps: In Pursuit of a Diagnostic/Drug Pairing
Looking ahead, the researchers envision the possibility of identifying patients with the biomarker, which could lead to additional testing indicating whether or not there is underlying inflammation or perturbations in the intestine. From there, a tailored therapeutic intervention could help delay the onset of disease—or perhaps even prevent it entirely.
Antibodies recognize specific regions on their target, and those regions were previously unknown, Mortha explained, so he and colleagues sought to find out what is recognized by these aGMAb antibodies.
They discovered that specific epitopes—parts of an antigen molecule to which an antibody attaches itself—are recognized and can be modified by engineering a new immune protein.
Notably, the group found they could maintain the protective effects of the GM-CSF cytokine by manipulating and improving its biochemical features. Their system makes it possible to see how the aGMAb antibodies offset GM-CSF in every patient, and they are working on creating cytokines designed to help patients avoid this neutralization.
“We can make a new immune protein that is basically invisible to these antibodies,” Mortha said, which could essentially bypass the biomarker’s neutralizing effects. “So this is a possibility to generate a therapeutic,” he added.
The approach could enable personalized therapies capable of reversing the effects of the antibodies and restoring immune balance within the intestine.
So what’s next? Mortha said a team of physicians and basic scientists has been assembled to characterize more patients. They will also attempt to better understand this biomarker’s behavior over the course of the disease and learn how treatments impact its behavior.
The researchers are working on testing a diagnostic assay that will impact how they design a therapeutic option for patients. The goal is to develop a medication that would be available in pill form rather than relying on injections.
Ideally, Mortha said, a diagnostic assay could identify the biomarker and be paired with an oral medication that would “hopefully prevent the outbreak of the disease and improve the immune system of those patients.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.