It has been suggested that serum leucine-rich α-2 glycoprotein (LRG) could be a novel monitoring biomarker for the assessment of disease activity in inflammatory bowel disease. In particular, the relationship between LRG levels and the endoscopically assessed activity of ulcerative colitis (UC) has become a matter of interest.

To clarify appropriate LRG cut-off values for the prediction of endoscopic and histologic remission in Japanese patients with UC.

This was a cross-sectional, single-center, observational study of Japanese patients with UC. Among 213 patients with UC, in whom LRG was measured from September 2020 to February 2022, we recruited 30 patients for whom a total colonoscopy and measurements of LRG and C-reactive protein (CRP) were performed on the same day. We retrospectively analyzed correlations between the LRG and CRP levels and endoscopic indices, including the Mayo endoscopic subscore and UC endoscopic index of severity.

Correlations between the LRG values and the Mayo endoscopic subscore or UC endoscopic index of severity were significant (r = 0.754, P < 0.0001; r = 0.778, P < 0.0001, respectively). There were also significant correlations between CRP levels and Mayo endoscopic subscore or UC endoscopic index of severity (r = 0.599, P = 0.0005; r = 0.563, P = 0.0012, respectively), although the correlation coefficients were higher for LRG. The LRG cut-off value for predicting endoscopic remission was 13.4 μg/mL for a Mayo endoscopic subscore of 0 [area under the curve (AUC): 0.871; 95% confidence interval (CI): 0.744–0.998], and 13.4 μg/mL for an UC endoscopic index of severity of 0 or 1 (AUC: 0.904; 95%CI: 0.792–1.000).

LRG may be a surrogate marker for endoscopic activity in UC, with a cut-off value of around 13.4 μg/mL for endoscopically inactive disease.

Mucosal healing (MH) has recently become an important treatment goal in ulcerative colitis (UC). The achievement of MH has been reported to decrease the recurrence, malignant transformation, hospitalization rates, and surgical requirements of various gastrointestinal disorders[1-5]. In addition, histological remission is superior to endoscopic healing in predicting long-term remission and cancer prevention[6-10]. The Selecting Therapeutic Targets in Inflammatory Bowel Diseases (IBD) IBD (STRIDE)-II initiative encompasses recommendations for treat-to-target strategies for adults and children with IBD[11]. STRIDE-II has recommended the use of clinical remission, C-reactive protein (CRP) normalization, and decreased fecal calprotectin levels as intermediate targets, with endoscopic remission and histological healing as long-term targets.

Serum leucine-rich α-2 glycoprotein (LRG) is a novel monitoring biomarker for the assessment of disease activity in IBD. LRG levels have been shown to reflect gastrointestinal inflammation[12-18]. However, appropriate LRG cut-off values have not been established in patients with UC. We thus aimed to investigate reasonable LRG cut-off values for predicting endoscopic and histologic activity in Japanese patients with UC.

LRG is a 50-kDa glycoprotein containing eight leucine-rich repeat domains. It has been reported to be a novel serum biomarker for the detection of rheumatoid arthritis and IBD[24]. The primary sites of LRG production are thought to be intestinal epithelial cells, neutrophils, and hepatocytes that are stimulated by interleukin (IL)-6, tumor necrosis factor-, and IL-22, among other cytokines[25,26]. CRP is a protein that is representative of acute phase reactants. The liver, under the stimulation of circulating IL-6, is the primary organ for CRP production[27]. Thus, it has been presumed that LRG is more sensitive than CRP for assessing the severity of inflammation in systemic diseases.

Several papers have reported that serum levels of LRG are correlated with endoscopic activity in patients with UC[12-18]. Shinzaki et al[14] recently published results of a prospective, observational study that evaluated serum LRG as a biomarker for disease activity in IBD (PLANET study). Their study found that serum LRG was a useful biomarker of endoscopic activity in patients with UC receiving adalimumab treatment[14]. A subanalysis of the PLANET study revealed that LRG, rather than CRP, may be a more accurate marker for predicting the trough level of adalimumab in patients with CD or UC[28].

Our study included 30 patients for whom total colonoscopy and measurements of LRG and CRP were performed on the same day. There were significant correlations between LRG levels and MES and LRG levels and UCEIS. There were also significant correlations between CRP levels and MES, and CRP levels and UCEIS, although the correlation coefficients were higher for LRG level. Thus, it seems possible that LRG is a candidate that is equal or, possibly, superior to CRP for the assessment of disease activity in UC.

The recommended cut-off value of LRG for the detection of active disease in patients with UC is regarded as 16 μg/mL. Subsequently, the cut-off value of the serum level of LRG for the detection of active disease in patients with UC was reported by other investigators. Horiuchi et al[15] reported that a serum LRG cut-off value of 10.8 g/mL could be a novel biomarker for identifying patients with active total or left-sided colitis[15]. Shimoyama et al[16] reported that the optimal LRG cut-off value for the detection of endoscopically active disease defined as MES ≥ 1 was 12.7 μg/mL[16]. Yoshida et al[17] reported that the cut-off value of LRG for MH with the identical definition was 16.3 μg/mL[17]. Another study by Yasutomi et al[18] showed that the LRG cut-off for complete MH defined as an MES of 0 was 13 μg/mL[18]. The cut-off value varies according to the definition of MH and to the study population, whereas our study revealed that the LRG cut-off value for the prediction of MH defined as an MES of 0 was 13.4 μg/mL and it was 12.9 μg/mL for the prediction of UCEIS of 0 or 1. These observations suggest that a cut-off value of LRG at around 13 μg/mL is appropriate for the prediction of MH in patients with UC.

We also showed that there were significant correlations between LRG level and two of the three widely accepted histological activity systems for UC, namely, the Matts grade and Riley score. This observation seems reasonable, because neutrophil infiltration is the main item for the assessment of activity. In contrast, we could not find a significant correlation between GHS and LRG. This may be explained by the fact that mucosal damage, rather than inflammatory infiltration, is the key histological finding. Thus, LRG may be representative of grade of inflammation in patients with UC. Also, it should be noted that the practical cut-off values of LRG for endoscopic remission and histological remission were similar, indicating the significance of LRG in clinical practice.

This study had several limitations. First, it was performed at a single center and involved a limited number of patients. Second, since it was a retrospective study, there were some variations in patient comorbidities, such as infectious colitis and rheumatoid arthritis, and in applied medications. Third, we could not compare LRG with fecal calprotectin, a reliable fecal biomarker for UC. The comparison of LRG with fecal calprotectin remains to be examined in future prospective studies.

Our analysis revealed that LRG is a biomarker for patients with UC with respect to clinical, endoscopic and histological prediction of remission, and that the cut-off value of LRG for each may be around 13 μg/mL. With the use of the appropriate cut-off value, LRG seems to be a biomarker that is more specific and more sensitive than CRP.