P0494 Serum regenerating islet-derived 3-alpha (REG3α) is a new prognostic biomarker in Crohn’s Disease
Authors: Claytor J , Bourgonje A R , Ibing S , Cohen L , Colombel J F , Ferrara J , Levine J E , Ungaro R C 
Published: January 2025

Background

Regenerating islet-derived 3-alpha (REG3α) is a serum biomarker that, alone or in combination with ST2 (suppressor of tumorigenesis 2), has been used to risk-stratify patients in primary treatment trials for acute graft-versus-host disease (aGVHD) due to its accurate prediction of 6-month non-relapse mortality (1-3). Serum REG3α reflects Paneth cell function and intestinal stem cell niche integrity (4). Given the similarities between intestinal manifestations of aGVHD and Crohn’s disease (CD), we aimed to evaluate the prognostic value of REG3α in CD.

Methods

We enrolled 231 patients with CD on the Mount Sinai Crohn’s Colitis Registry (MSCCR) at the time of scheduled endoscopic evaluation. We prospectively collected baseline serum samples, and longitudinal clinical data were extracted from structured electronic health records [Table 1]. We used multivariable logistic regression models to investigate associations of IBD progression events, defined as hospitalization, surgery, steroid course, or new biologic, with baseline REG3α levels, controlling for clinical variables [age, biologic use, surgical history, Montreal classification, C-reactive protein (CRP), and endoscopic disease activity (Simple Endoscopic Score, or SES-CD)]. We derived a cutpoint via Youden’s Index to designate high- and low-risk groups by REG3α and used log-rank tests to uncover any difference in times-to-IBD progression event.

Results

Adjusting for SES-CD, CRP, and age, serum REG3α levels independently associated with adverse IBD outcomes (aOR 1.88, 95% confidence interval [CI] 1.16-3.04, p=0.01)). In subgroups of patients in endoscopic remission (n=124) or with remission+mild endoscopic disease (n=160), REG3α still significantly associated with IBD progression events (aOR 1.89 (95% CI: 1.05-3.39, p=0.034) for SES-CD&lt;3; aOR 1.84 (95% CI: 1.14-3.00, p=0.013) for SES-CD&lt;7). We used Youden’s index to derive a prognostic REG3α cutpoint of 30.29 ng/mL, with sensitivity 0.63 and specificity 0.62, to identify patients at risk of adverse IBD outcomes. High REG3α above the cutpoint conveyed increased hazards of IBD disease progression events (HR 1.91 (95%CI 1.33-2.75, p&lt;0.001 via log-rank test, Figure 1) at median 6.5 (interquartile range (IQR), 3-8) years of follow-up.

Conclusion

REG3α has potential as a non-invasive, prognostic biomarker in CD, independent of endoscopic inflammation. Elevated REG3α levels were associated with an increased risk of IBD-related disease progression events, including shorter time until IBD surgery, hospitalization, steroid course, or biologic use.

References

(1)Ferrara JLM, Harris AC, Greenson JK, et al. Regenerating islet-derived 3-alpha is a biomarker of gastrointestinal graft-versus-host disease. Blood. 2011;118(25):6702-6708. doi: 10.1182/blood-2011-08-375006

(2)Major-Monfried H, Renteria AS, Pawarode A, et al. MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD. Blood. 2018;131(25):2846-2855. doi:10.1182/blood-2018-01-822957

(3)Marafini I, Di Sabatino A, Zorzi F, et al. Serum regenerating islet-derived 3-alpha is a biomarker of mucosal enteropathies. Aliment Pharmacol Ther. 2014;40(8):974-981. doi:10.111/apt.12920

(4)Zhao D, Kim YK, Jeong S, et al. Survival Signal REG3a prevents crypt apoptotsis to control acute gastrointestinal graft-versus-host disease. J Clin Invest. 2018;128(11):4970-4979. doi:10.1172/JCI99261