TOPLINE

High serum regenerating islet-derived 3-alpha (REG3-alpha) levels were associated with an increased risk for Crohn's disease (CD) progression and complicated CD — even in patients with mild or inactive disease and up to 10 years before diagnosis. Notably, REG3-alpha flagged this risk independently of standard tests such as C-reactive protein (CRP) and endoscopy.

METHODOLOGY

• Researchers investigated whether serum REG3-alpha — a Paneth cell-derived protein — could serve as a prognostic biomarker for CD, using two prospective cohorts: the Mount Sinai Crohn's and Colitis Registry (MSCCR; n = 231) and the Leuven cohort (n = 163). Patients from the cohorts were followed up for a median of 9.8 years and 6.3 years, respectively.
• A separate prediagnostic cohort of 184 individuals who later developed CD and 89 matched healthy control individuals was also analyzed, using serum samples collected up to 10 years before diagnosis.
• Serum REG3-alpha was measured in the MSCCR and Leuven cohorts, and as normalized protein expression in the prediagnostic cohort; transcriptomic analyses were also used to characterize Paneth cell gene expression profiles and REG3-alpha production in patients with CD.
• The prospective cohorts' primary endpoint combined several markers of worsening disease — a hospital stay, surgery, starting steroids, or beginning a new biologic — all tied to active CD.
• In the prediagnostic cohort, complicated CD was defined by the onset of a stricture, a fistula, or the need for CD-related surgery.

TAKEAWAY

• REG3-alpha was associated with CD progression, independent of endoscopic disease activity and CRP in both cohorts. High serum REG3-alpha levels (> 30.3 ng/mL) were associated with a significantly higher risk for CD progression in both the MSCCR cohort (hazard ratio [HR], 1.9; P < .001) and the Leuven cohort (HR, 3.2; P < .001).
• Among patients with mild or inactive CD (Simple Endoscopic Score-CD < 7), high serum REG3-alpha levels remained associated with CD progression in both the MSCCR and Leuven cohorts (adjusted HR, 1.5; P = .025 and adjusted HR, 2.6; P = .003, respectively), whereas CRP levels did not.
• In the prediagnostic cohort, patients who developed CD had significantly higher serum REG3-alpha levels than healthy control individuals at every timepoint up to 10 years before diagnosis, with levels highest in those who went on to have complicated (vs uncomplicated) CD; REG3-alpha alone predicted complicated CD 6-10 years before diagnosis with an odds ratio of 3.0 and an area under the curve of 0.72.
• Single-cell RNA-sequencing showed that CD shifted ileal Paneth cells away from stem-cell-supportive, reparative populations toward inflammatory, hypersecretory subtypes — even in non-inflamed tissue — suggesting a mechanism by which this functional decline could drive rising serum REG3-alpha and, in turn, higher risk for CD progression.

IN PRACTICE

"Taken together, [the] findings suggest that REG3-alpha may serve not only as a dynamic inflammatory biomarker, but also as a tool for risk stratification, reflecting fundamental disease biology linked to Paneth cell dysfunction," the authors wrote.

SOURCE

The study was led by Jennifer D. Claytor, Icahn School of Medicine at Mount Sinai, New York City. It was published online in Clinical Gastroenterology and Hepatology.

LIMITATIONS

The study primarily included White participants and the prediagnostic cohort included more men than women, which may have limited the generalizability of the findings to other populations. The researchers did not assess the gut microbiome, limiting evaluation of microbial changes that may be linked to elevated REG3-alpha levels.

DISCLOSURES

The study was supported by grants from the Leona M. and Harry B. Helmsley Charitable Trust to Icahn School of Medicine at Mount Sinai Hospital. One author received support from the National Institute of Diabetes and Digestive and Kidney Diseases. One author is an employee of the US government. Several authors declared receiving consulting fees, research support, or honoraria from or holding advisory board roles in multiple companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.