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Crohn’s Disease Biomarker Appears Years Ahead of Diagnosis

Anti–granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies predict complicated Crohn’s disease (CD) years before signs or symptoms of the disease appear, according to new data.

A study of records from active military personnel indicates that this novel biomarker holds promise for the diagnosis, management, and treatment of complicated CD.

“To the best of my knowledge, this is the first sole biomarker predicting complicated CD,” lead author Arthur Mortha, PhD, assistant professor of immunology at the University of Toronto, Ontario, told Medscape Medical News.

The study was published online May 24 in Gastroenterology.

Six Years’ Warning

A break in intestinal homeostasis is a key immunologic characteristic of inflammatory bowel disease (IBD), of which CD is one type. This break appears in the forms of insufficient barrier integrity, reduced immunologic tolerance, and excessive inflammation.

GM-CSF plays a role in intestinal inflammation. Previous studies showed that it can induce and dampen inflammation in CD. Lymphoid cells in the gut produce GM-CSF, which in turn regulates myeloid immune cells to maintain immune homeostasis. Genetic defects in GM-CSF signaling and autoantibodies against GM-CSF are associated with greater disease severity and more frequent relapses in patients with CD.

The researchers used enzyme-linked immunosorbent assay (ELISA) to analyze levels of anti-GM-CSF autoantibodies among 220 individuals who subsequently received a diagnosis of CD and among 400 healthy control persons. Participants were drawn from the US Defense Medical Surveillance System. The analysis included data from over 1800 sera samples.

The autoantibodies target posttranslational modifications of GM-CSF (specifically, glycosylation), and the researchers observed abnormal glycosylation of GM-CSF in patients with CD. The first signs of these antibodies appeared as early as 6 years before diagnosis in symptomatic individuals, and they predicted complications at the time of disease presentation (hazard ratio, 2.9; P < .001). The antibodies interfered with communication between group 3 innate lymphoid cells (ILC3), which produce GM-CSF in the gut, and myeloid cells in the noninvolved CD mucosa. This interference was associated with changes to gene signatures found in ILC3 cells.

The new biomarker could complement other prodromal signs of early or aggressive CD, such as antibodies that target specific microbial antigens and intestinal permeability. “Anti-GM-CSF autoantibodies are detected prior to the occurrence of microbial antibodies. Combining additional markers and tests prior to diagnosis may be a good way to strengthen the prediction and possibly serve as a new method to determine the time that remains until the disease will be diagnosed,” said Mortha.

He noted that the findings need to be repeated in a larger prospective study among individuals at heightened risk of CD. Such a study is now being planned. “Our results and refined understanding of this biomarker do now allow us to develop specialized diagnostic assays and tailored therapeutics. We hope to have these ready for their first tests in the near future,” said Mortha.

Diagnosis and Prognosis

Commenting on the study for Medscape, Miguel Regueiro, MD, chair of the Digestive Disease and Surgery Institute and a professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, said, “This study found a fascinating finding of an immune dysregulation early in the Crohn’s disease process well before a person developed signs or symptoms. [Researchers] need larger prospective population-based data. However, this work is unique and impactful and could change the way we diagnose and treat IBD.”

Taken together, the mechanistic findings may inform future therapeutic development. “Given the immune dysregulation, the researchers also explored the possibility of interrupting this immune defect and could potentially uncover a new way of treating Crohn’s in the future,” said Regueiro.

For example, the researchers speculate that GM-CSF could be engineered to escape anti-GM-CSF autoantibody activity, which could allow the restoration of homeostasis or slow disease progression. They call for clinical trials of modified GM-CSF in patients selected for their expression of autoantibodies to GM-CSF.

More immediately, the study could have implications for patient management. “I think this could be useful in high-risk patients — for example, those with family histories of IBD or those who develop nonspecific gastrointestinal symptoms earlier in life and are often confused with irritable bowel syndrome. We need more data on whether this will be a biomarker to follow during disease course.”

Anti-GM-CSF autoantibodies could become a biomarker of diagnosis and prognosis, Regueiro added. “Finally, it’s possible that this could lead to specialized treatment that is targeted to the patients with this biomarker. This could be the precision medicine to improve remission rates to much higher than we see today with our current therapies.”

The study was funded by grants from the Canadian Institutes of Health Research, the Natural Sciences and Engineering Research Council of Canada and the Helmsley Foundation. Mortha and Regueiro have disclosed no relevant financial relationships.

Gastroenterology. Published online May 24, 2022. Abstract

Jim Kling is a science and medical writer in Bellingham, Washington.

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