Corresponding author: Koji Takahashi, koji517@gmail.com
DOI: 10.31662/jmaj.2026-0039
Received: January 26, 2026
Accepted: February 18, 2026
Advance Publication: April 24, 2026
Key words: Crohn's disease, leucine-rich α2 glycoprotein, small bowel, biological agents, mucosal healing
I read with great interest the article by Hayashi et al. (1) regarding the utility of leucine-rich α2 glycoprotein (LRG) as a predictor of small bowel disease activity in Crohn’s disease (CD). The authors should be commended for conducting a large-scale study using balloon-assisted enteroscopy as the gold standard―a rigorous approach that provides high-quality evidence in a region that is notoriously difficult to evaluate. Their finding that LRG outperforms C-reactive protein (CRP) in detecting small bowel lesions aligns with the evolving “tight control” strategy in CD management (2).
However, while the diagnostic performance of LRG (area under the curve 0.906) is impressive, I have concerns regarding the generalizability of these findings, particularly the potential confounding influence of concomitant medical therapies on LRG expression.
The study reports a median Crohn's disease activity index of 104.4, suggesting that most of the cohort was in clinical remission or had mild disease activity. While biomarkers are indeed most valuable in detecting “silent” inflammation, the performance of LRG in a cohort with more severe clinical activity remains to be fully elucidated. More importantly, the authors do not provide detailed data on the patients’ concurrent medications, such as tumor necrosis factor (TNF) antagonists, interleukin (IL)-23 inhibitors, or Janus kinase inhibitors.
LRG is induced by TNF-α, IL-1β, and IL-22 via pathways independent of IL-6, which distinguishes it from CRP (3). However, it is precisely this cytokine-specific induction that raises questions regarding its consistency across different treatment classes. Evidence suggests that different biologics may modulate LRG levels disparately; for instance, IL-23 inhibitors directly impact the IL-22 pathway, which could theoretically lead to a “biomarker-endoscopic dissociation” where LRG levels decrease before complete mucosal healing is achieved (4). Conversely, in patients refractory to multiple cytokine-targeted therapies, LRG might remain elevated due to redundant inflammatory pathways (5).
I would, therefore, welcome the authors’ insights on two points: First, did the diagnostic accuracy of the 16.3 μg/mL cutoff remain consistent when stratified by treatment class (e.g., anti-TNF vs. anti-IL-23)? Second, was there any significant difference in LRG performance between treatment-naive patients and those with long-standing, refractory disease?
Refining our understanding of how specific therapeutic interventions influence LRG expression is essential before this promising biomarker can be universally adopted as a surrogate for invasive enteroscopy in clinical practice.
Conceptualization, and writing original draft: Koji Takahashi.
None
Not applicable.
Hayashi T, Kitamura K, Usami M, et al. Leucine-rich α2 glycoprotein as a predictor of small bowel disease activity in Crohn’s disease: a retrospective study. JMA J. 2026;9(1):225-33.
Turner D, Ricciuto A, Lewis A, et al. STRIDE-II: an update on the selecting therapeutic targets in inflammatory bowel disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Gastroenterology. 2021;160(5):1570-83.
Serada S, Fujimoto M, Terabe F, et al. Serum leucine-rich alpha-2 glycoprotein is a disease activity biomarker in ulcerative colitis. Inflamm Bowel Dis. 2012;18(11):2169-79.
Shinzaki S, Matsuoka K, Iijima H, et al. Leucine-rich alpha-2 glycoprotein is a serum biomarker of mucosal healing in ulcerative colitis. J Crohns Colitis. 2017;11(1):84-91.
Kawamoto A, Takenaka K, Hibiya S, et al. Serum leucine-rich α2 glycoprotein: a novel biomarker for small bowel mucosal activity in Crohn’s disease. Clin Gastroenterol Hepatol. 2022;20(5):e1196-200.
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