Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis

Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis Yuki Aoyama, Sakiko Hiraoka, Eriko Yasutomi, Toshihiro Inokuchi, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4231663/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Leucine-rich alpha 2 glycoprotein (LRG) is one of the promising serum biomarkers for disease activity of ulcerative colitis (UC). However, several previous reports suggested that the correlation of absolute values of LRG with endoscopic/histologic activity was superior to that of CRP but inferior to those of fecal markers. Here, we focused on the correlation between the changes of LRG and the changes of endoscopic and histologic activity of UC, in comparison to the changes of fecal calprotectin (Fcal), fecal immunochemical test (FIT), and C-reactive protein (CRP). Patients with UC who underwent two or more colonoscopies were enrolled. The comparison of the changes in marker levels with the change of endoscopic/histologic activity in 123 paired colonoscopies of 79 patients revealed that the strength of the correlation in LRG (r = 0.42/0.40) was almost similar to that of fecal markers (Fcal; r = 0.50/0.39 and FIT; r = 0.41/0.40) and better than that of CRP (r = 0.22/0.17). LRG is equivalent to fecal markers and superior to CRP, when inferring changes in disease activity of UC based on changes in its level. Health sciences/Biomarkers/Predictive markers Health sciences/Biomarkers/Prognostic markers Health sciences/Gastroenterology/Colonoscopy Health sciences/Gastroenterology/Gastrointestinal diseases Ulcerative colitis Leucine-rich alpha 2 glycoprotein Biomarker Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Ulcerative colitis (UC) is a chronic, refractory inflammatory bowel disease (IBD) of unknown cause and can be diagnosed based on clinical evaluation and a combination of hematological, endoscopic, histological, or imaging-based investigations 1 . Clinical remission has been the primary target of treatment; however, endoscopic remission, which means that endoscopy shows no mucosal inflammation, has recently been recognized as more appropriate 2 . For this purpose, endoscopic evaluation would be desirable to accurately evaluate disease activity. However, the significant physical and economic burdens make it difficult to perform frequent endoscopic examinations. As an alternative, serum and/or stool markers, such as serum C-reactive protein (CRP), fecal calprotectin (Fcal) and fecal immunochemical test (FIT), have been studied as inflammatory markers for inferring the disease activity 3 – 5 . Although stool testing is useful, compliance is hampered in some patients 6 – 8 . In this point, blood tests are simpler examinations for all patients than fecal tests. However, because serum CRP levels are not always informative in patients with UC 9 , the monitoring of serum CRP is not adequate for assessing the disease activity of UC. Therefore, there is a strong need for new reliable serum markers for inferring the disease activity of UC. Serum leucine-rich alpha 2 glycoprotein (LRG) is a substance obtained by proteomic screening from patients with rheumatoid arthritis (RA) 10 . Unlike CRP, LRG is induced not only by IL-6 but also by other proinflammatory cytokines 10 , 11 , and is expressed not only in liver but also in local inflammatory sites, produced by neutrophils, macrophages, hepatocytes, and intestinal epithelial cell 12 – 14 . Indeed, serum LRG was reported to be more strongly correlated with the disease activity of RA in comparison to serum CRP 15 . In the case of IBD, the serum LRG levels are higher in patients with active-phase UC 15 . Therefore, serum LRG can be a good candidate as a novel serum marker for evaluating the disease activity of UC 16 – 18 , which may be clinically beneficial. However, there are a few reports that the correlation between LRG values and endoscopic/histologic activity was better than CRP, but inferior to fecal markers such as Fcal and FIT 16 , 17 . Therefore, the best way to use this marker to evaluate the disease activity of UC during the chronic course in the clinical setting has not been determined. In some biomarkers, because the baseline levels may differ among individuals, focusing on the changes in the levels during the course of chronic diseases may be more useful than focusing on the absolute value at one analysis point. In fact, the changes in the level of Fcal more precisely reflect the changes in endoscopic activity than those in FIT; this was revealed by focusing on the changes in values during the disease course 19 . Previous reports have assessed that LRG correlated with UC activity at one analysis point 16 , 17 , but have not assessed the correlation between the changes in LRG levels and colonic mucosal activity including comparisons with other biomarkers. Therefore, in this study, we focused on the changes in biomarker levels between paired colonoscopy tests during the management of patients with UC, to determine how these biomarkers, including the serum LRG level, can be better used. Methods 1. Patients Since November 2015, we have continuously asked patients with UC who were scheduled for colonoscopy at Okayama University Hospital to provide fecal and serum samples at the same time as the colonoscopy for the purpose of analyzing correlations between biomarkers and endoscopic/histologic activity. Building on our previous study 19 , this study aimed to analyze the correlation between changes in colonic mucosal activity and changes in fecal and serum marker levels between two colonoscopies. Therefore, patients who underwent two or more colonoscopies and provided samples between November 2015 and November 2021 were included. In the patients who underwent more than three colonoscopies during the study period, data between two consequent colonoscopy tests were compared. The exclusion criteria were insufficient stool collection or the failure to achieve full endoscopic observation of the patients’ lesions. Patients with other diseases that could affect the serum levels of LRG and CRP (i.e., extraintestinal complications, infectious disease, collagen disease, primary biliary cholangitis, heart failure, or malignancy) at the time of endoscopy were excluded. 2. Assessment of the endoscopic disease activity Colonic mucosal activity was assessed by endoscopic disease activity and pathologic activity of tissue obtained at the time of colonoscopy. All patients in this study received bowel preparation with a polyethylene glycol-based or magnesium citrate-based electrolyte solution for colonoscopy according to the standard protocol in our hospital. According to the results of colonoscopy, disease activity was evaluated by assigning the Mayo Endoscopic Subscore (MES) to the sites with the most severe mucosal inflammation. The MES was evaluated using a four-point scale (0–3). An MES 0–1 was defined as endoscopic remission, while MES 2–3 was defined as endoscopic active-phase disease 20 . Change from endoscopic remission (MES 0–1) to endoscopic active-phase disease (MES 2–3) was defined as endoscopic relapse. Without referring to the medical records and results of the fecal and serum markers at the time of colonoscopy, the MES was assessed by two independent endoscopy specialists. 3. Pathologic scoring Pathological activity was scored by gastrointestinal pathologists using the Geboes score 21 . The Geboes score is classified into 6 grades from grade 0 to grade 5. Histological remission is defined as Geboes score < 2.1. The biopsy specimen used for the evaluation of histopathological activity was obtained from the site with maximum endoscopic activity, while for remission cases, a biopsy specimen from the rectum was analyzed. When one or more biopsy specimens were evaluated in each patient, the highest score was used for the analyses. 4. Serum sampling and analyses Blood samples were collected from all patients for the determination of the serum LRG and CRP levels on the day of endoscopy. Serum samples for LRG measurement were stored at -80°C until use. LRG was measured in bulk later at our institution using a NANOPIA LRG kit (SEKISUI MEDICAL, Tokyo, Japan) 16 . Serum CRP was measured at our institution using a NANOPIA CRP kit (SEKISUI MEDICAL, Tokyo, Japan) on the day of colonoscopy. The measurement range of this high-sensitivity kit was from 0.01 mg/dL to 42 mg/dL. 5. Fecal sampling and analyses Patients were requested to prepare two fecal samples within 2 days before colonoscopy for the examination of calprotectin and FIT. Fecal samples collected by the patients were stored at − 30°C until shipment to the BML (Tokyo, Japan), where the level of calprotectin in the fecal specimen (Fcal) was measured with a fluorescence enzyme immunoassay using Phadia EliA Calprotectin 2 (Thermo Fisher Scientific, Phadia AB, Uppsala, Sweden). The FIT was performed at our institution using an OC-Sensor DIANA or PLEDIA system (Eiken Chemical, Tokyo, Japan) with stool samples collected with a Hemodia sampling probe (Eiken Chemical) 16 . Because the FIT is not accurate for measuring hemoglobin concentrations of < 50 ng/mL, the specimens with a hemoglobin concentration within this range (0–50 ng/mL) were all treated as 50 ng/mL in this study. 6. Statistical Analyses The characteristics of patients were described with numbers and percentages for categorical variables, indicating the mean standard deviation or median (range) for continuous variables according to the distribution. Spearman’s rank correlation test was used for determining the correlations between the levels of serum/fecal markers and the MES or Geboes scores. Receiver operating characteristic (ROC) analyses were used to assess the cut-off values of serum/fecal markers between the endoscopic status of MES 0–1 and MES 2–3 and the histological status of Geboes score < 2.1 and Geboes score ≥ 2.1. The results were expressed as the area under the curve (AUC), with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy with 95% confidence intervals. Two-sided p values of < 0.05 were considered to indicate statistical significance. 7. Ethical considerations This study was approved by the Institutional Review Board of Okayama University Graduate School of Medicine (IRB number: 1904-035) and conducted in accordance with the Declaration of Helsinki. All research was performed in accordance with the relevant guidelines/regulations. Informed consent was obtained from each patient and/or their legal guardians. Results 1. Clinical characteristics of the patients Two hundred twenty-nine patients with UC were registered and 352 endoscopic examinations were performed during the observation period. Seventy-nine of the registered patients underwent colonoscopy tests more than once and provided fecal/serum samples. The characteristics of the 79 enrolled patients, the colonoscopy findings, and the values of biomarkers are summarized in Table 1 (Table 1 ). Forty male and thirty-nine female patients with a median (range) age of 48.0 years (37.5–57.6 years) were included in the study. The median (range) age at the onset of the disease was 36.4 years (25.3–45.2 years old), and the median (range) disease duration was 9.8 years (3.8–16.8). There were 52 cases of extensive colitis (65.8%), 22 cases of left-sided colitis (27.8%), 4 cases of proctitis (5.1%), and 1 case of right-sided colitis (1.3%). For the analysis of the changes of endoscopic activity and biomarkers, the maximum MES for the colorectum, as determined based on the precedent findings of 123 paired colonoscopic, was as follows: MES 0, n = 51 (41.4%); MES 1, n = 35 (28.5%); MES 2, n = 28 (22.8%); and MES 3, n = 9 (7.3%). The interval between the two consecutive colonoscopy tests that were used for the analyses of data was 15.4 months (11.7–25.6 months). Table 1 Characteristics of the enrolled patients, colonoscopy findings, and biomarker values Patients n = 79 Sex, n (%): male / female 40 (50.6)/ 39 (49.4) Median (range) age at precedent colonoscopy, years Median (range) age at the onset of the disease, years 48.0 (37.5–57.6) 36.4 (25.3–45.2) Median (range) disease duration at precedent colonoscopy, years 9.8 (3.8–16.8) Disease location, n (%) Extensive/ Left-sided/ Proctitis/ Right-sided 52 (65.8)/22 (27.8)/4 (5.1)/1 (1.3) Analyzed colonoscopic pairs, 1/ 2/ 3/ 4 51/ 17/ 6/ 5 Colonoscopies (paired) n = 123 Activity assessment at the precedent colonoscopy Mayo endoscopic subscore, n (%): 0/ 1/ 2/ 3 51 (41.4)/35 (28.5)/28 (22.8)/9 (7.3) *Geboes score, n (%): 0/1/2/3/4/5 17 (14.0)/38 (31.4)/12 (9.9)/ 16 (13.2)/17 (14.0)/21 (17.5) Values of biomarkers, median (range) at the precedent colonoscopy Fecal calprotectin, ng/mL 119 (31–447) Fecal immunochemical test, ng/mL 50 (50–315) Leucine-rich alpha 2 glycoprotein, µg/mL 12.6 (10.1–14.9) C-reactive protein, mg/dL 0.08 (0.04–0.19) Median (range) interval between the precedent and subsequent colonoscopy, months 15.4 (11.7–25.6) *Two colonoscopies, no biopsies were taken. The treatments of the 79 patients are shown in Table 2 (Table 2 ). Of 123 paired cases, medication was changed between the precedent and subsequent colonoscopic examinations in 48 pairs (39.0%). Immunosuppressive medication was introduced for the 14 pairs (11.4%) and interrupted in 19 pairs (15.4%) (Supplemental Table 1). Table 2 Medication at the precedent colonoscopy Concomitant medication at the precedent colonoscopy, n (%) 5-aminosalicylic acid, oral agent / suppository 67 (84.8) / 17 (21.5) Steroid, oral agent / suppository 7 (8.9) / 3 (3.8) Immunomodulator 35 (44.3) Anti-tumor necrosis factor-α agents 9 (11.4) Vedolizumab 3 (3.8) Janus kinase inhibitor 1 (1.3) Tacrolimus 4 (5.1) Indigo naturalis 5 (6.3) 2. Correlation between the changes in the MES and biomarker levels The changes in the endoscopic activity scores in 123 intervals from the consecutive colonoscopic examination are shown in Fig. 1 . During the intervals of the two consecutive examinations, 29 showed improved MES values, 63 showed unchanged MES values, and 31 showed worsened MES values (Fig. 1 ). The changes of the fecal and serum marker levels in the improved, unchanged, and worsened groups, respectively, were as follows: Fcal. -167 (-1054–0) µg/g, 0 (0–64.5) µg/g, 69 (0–766.5) µg/g; FIT, -150.4 (-911 - -13.7) ng/mL, -10.9 (-112.6–64.0) ng/mL, 158.9 (-20.0–1132) ng/mL; LRG, -2.1 (-5.1 - -0.11) µg/mL, -0.08 (-1.4–2.2) µg/mL, 1.5 (0.28–5.4) µg/mL; and CRP, -0.035 (-0.18–0.038) mg/dL, 0.005 (-0.038–0.07) mg/dL, 0.01 (-0.02–0.07) mg/dL. Spearman’s rank correlations between the changes of MES and the changes of fecal/serum marker levels were as follows; Fcal, r = 0.50, p < 0.0001; FIT, r = 0.41, p < 0.0001; LRG, r = 0.42, p < 0.0001; and CRP, r = 0.22, p = 0.013 (Fig. 2 )༎These results suggested that the changes in LRG were significantly more strongly correlated with the changes in endoscopic activity than the changes in CRP levels. In addition, the cut-off values of change of each biomarker for endoscopic relapse were examined based on 86 cases of MES 0–1 at the first colonoscopy. Of these, 66 cases remained MES 0–1, while 20 cases showed relapse (MES 2–3) at the second colonoscopy. The cut-off values for fecal and serum markers were shown the supplemental material (Supplemental Table 2). 3. Correlation between the changes in Geboes score and the changes in biomarker levels Because no biopsy specimens were obtained in 2 colonoscopy tests, 121 paired cases were analyzed pathologically. Among 121 cases, 45 paired cases showed improved Geboes scores (ΔGeboes score: -4, n = 5; -3, n = 7; -2, n = 11; -1, n = 22), 36 showed unchanged scores: (ΔGeboes score 0), and 40 showed worsened Geboes scores (ΔGeboes score: 1, n = 13; 2, n = 13; 3, n = 9; 4, n = 5). The changes in the fecal/serum markers of the improved, unchanged, and worsened groups, respectively, were as follows: Fcal, -99 (-249–1.0) µg/g, -27 (-148–26) µg/g, 114 (3.0–784) µg/g; FIT, 0 (-828–0) ng/mL, 0 (0–15) ng/mL, 28 (0–785) ng/mL; LRG, -1.0 (-5.0–0.23) µg/mL, -0.11 (-1.93–2.16) µg/mL, 1.45 (0.08–4.53) µg/mL; and CRP, -0.01 (-0.08–0.04) mg/dL, 0 (-0.09–0.06) mg/dL, 0.02 (-0.02–0.09) mg/dL. Spearman’s rank correlations between the changes in the Geboes score and the changes in fecal/serum marker levels were as follows: Fcal, r = 0.39, p < 0.0001; FIT, r = 0.40, p = 0.028; LRG, r = 0.40, p < 0.0001; CRP, r = 0.17, p = 0.06 (Fig. 3 ). These results suggested that the changes in LRG were similarly correlated with the fecal markers and significantly more strongly correlated with the changes in histological activity than those in CRP levels. 4. Correlation between the MES and the fecal/serum marker levels at 202 time points The correlation between the MES and each biomarker level at 202 time points in 123 paired cases is shown in Fig. 4 . One hundred fifty-two (75.2%) of 202 colonoscopies showed no or mild endoscopic activity (MES 0 or 1). Spearman’s rank correlations between the MES and the fecal/serum marker levels were as follows: Fcal, r = 0.53, p < 0.0001; FIT, r = 0.62, p < 0.0001; LRG, r = 0.32, p < 0.0001; and CRP, r = 0.25, p < 0.001. The detectability of endoscopic remission (MES 0–1) in the ROC analysis is also shown (Supplemental Table 3). The cut-off values of LRG for endoscopic remission (MES 0–1) was 14.8 µg/mL. These results suggested that fecal marker levels were more strongly correlated with the endoscopic activity than the serum markers at a single time point of measurement and had higher diagnostic rates, especially in determining endoscopic remission. 5. Correlation between the Geboes score and the fecal/serum marker levels at 202 time points The correlations between the Geboes score and each biomarker level at 202 time points in 123 paired cases is shown in Fig. 5 . Spearman’s rank correlations between the Geboes score and the fecal/serum marker levels were as follows: Fcal, r = 0.40, p < 0.0001; FIT, r = 0.27, p < 0.0001; LRG, r = 0.34, p < 0.0001; and CRP, r = 0.18, p = 0.0094. The detectability of histological remission (Geboes score < 2.1) in the ROC analysis of each biomarker is shown in Supplemental Table 4. The cut-off value of LRG for histological remission (Geboes score < 2.1) was 12.6 µg/mL. These results suggested that LRG was more strongly correlated with the histological activity than CRP. Discussion Our study showed that the changes in serum LRG between two consecutive colonoscopy tests were significantly correlated with the changes in the endoscopic and histologic activity, when presently available serum biomarkers are not sufficiently effective for monitoring the disease activity. To our knowledge, our results are unique in real-world clinical practice, in the point of view that comparing the changes in the serum LRG/CRP levels and the Fcal/FIT levels with the changes in the endoscopic and histologic scores in the same UC patient. determined the correlation between serum LRG and the disease activity of UC using single-point analyses 16 , 17 . In addition, the comparison of the biomarkers including LRG with findings of multiple endoscopies has already been reported and discussed in a previous well-conceived prospective report 18 . In contrast to the previous studies, our report has the following advantages. First, most of our patients were in remission or mild disease in outpatient settings that enabled validation of usefulness of LRG in real clinical practice with not so large changes in disease activity. Second, all analyzed biomarkers including FIT, which was clinically useful but was not examined in the previous reports, were compared to the endoscopic and histologic findings. The results that the changes in the serum LRG had a strong correlation in with the trend in UC activity, similarly to fecal markers, are meaningful for daily clinical practice. Based on the above results, we propose the following usage of each biomarker in clinical practice related to UC. In cases with high activity (MES2-3) during the induction period, CRP has been reported to be more strongly correlated with the MES in comparison to fecal markers 22 , 23 . The heterogeneity in fecal samples in cases of diarrhea due to excessive disease activity may make measurements inaccurate. In these situations, however, LRG could be useful because CRP are likely to be negative during remission induction despite residual endoscopic activity. In cases with low disease activity (MES 1), such as those with mild inflammation without clinical symptoms, serum CRP levels are often negative and are not useful 9 . On the other hand, Fcal and FIT may be significantly correlated with the change from low disease activity to remission (MES 0–1) 19 , 23 , 24 . Based on the present study, the examination of serum LRG may also be useful for these cases. Especially when fecal markers do not show any significant decrease despite appropriate therapeutic intervention, the combined use of the changes in serum LRG with fecal markers may be useful because fecal markers yield false positive results due to the use of non-steroidal anti-inflammatory drugs, the presence of hemorrhoids, inflammatory polyps, colonic diverticulum, the infection with bacteria or viruses, the diurnal variation, or menstruation in women 25 – 30 . In determining endoscopic remission (MES 0) and assessing the maintenance of MES 0, fecal markers may be more useful than serum LRG 4 , 5 . However, once fecal markers become elevated with or without symptom relapse, the examination of changes in serum LRG may be useful for assessing the changes in disease activity. The present study was associated with several limitations. First, since this was a single-center study, confirmation by multi-center studies is desirable. Second, the population was biased toward patients with relatively low inflammation (MES 0–1). Similar studies should be conducted that include cases with high inflammation (MES 2–3). Third, the intervals of colonoscopy and biomarker examinations were not fixed and different among individuals. Fourth, all cases with fecal hemoglobin concentrations of < 50 ng/mL were treated as 50 ng/mL in this study. More accurate data may be necessary for patients with hemoglobin concentrations of < 50 ng/mL. In conclusion, the examination of the changes in serum LRG may be more useful and accurate than serum CRP for assessing the changes of UC disease activity, and shows similar clinical significance to the examination of fecal markers. Measurement of serum LRG can be performed by simple blood collection. Hence, LRG may have utility in the management of the chronic course of UC. Abbreviations UC ulcerative colitis IBD inflammatory bowel disease CRP C-reactive protein Fcal fecal calprotectin FIT fecal immunochemical test LRG leucine-rich alpha 2 glycoprotein RA rheumatoid arthritis MES Mayo endoscopic subscore ROC Receiver Operating Characteristic AUC area under the curve PPV positive predictive value NPV negative predictive value. Declarations Conflicts of Interest: The authors declare no conflict of interest. Funding: This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#20K12669 to S.H. and #22H02828 to M.O.). Author Contribution Conceptualization: S.H.; Methodology: Y.A., S.H.; Formal analysis and investigation: Y. A., S.H., Y.Y.; Writing - original draft preparation: Y.A., S.H.; Writing - review and editing: Y.A., S.H., T.I., T.T., K.Takei., S.I., K.Takeuchi., M.T., J.T., H.K.; Resources: Y. A., E.Y.; Supervision: H.O., J.K., M.O. All authors have read and approved the final version to be published. Acknowledgement We would like to thank Mr. Masanori Furukawa for their efforts in measuring serum LRG samples. We are also thankful to Ms. Mayumi Tokumitsu for her invaluable help in data input. Data Availability The data underlying this article will be shared on reasonable request to the corresponding author and it is provided within the manuscript or supplementary information files. References Mowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 60 , 571-607 (2011). Frøslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 133 , 412-422 (2007). Yoon JY, Park SJ, Hong SP, Kim TI, Kim WH, et al. Correlations of Creactive protein levels and erythrocyte sedimentation rates with endoscopic activity indices in patients with ulcerative colitis. Dig. Dis. 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Supplementary Files SRSupplementalMaterial.pdf Cite Share Download PDF Status: Published Journal Publication published 12 Feb, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 13 Nov, 2024 Reviews received at journal 24 Oct, 2024 Reviewers agreed at journal 09 Oct, 2024 Reviewers agreed at journal 26 Aug, 2024 Reviewers agreed at journal 20 Jul, 2024 Reviews received at journal 30 Jun, 2024 Reviewers agreed at journal 24 Jun, 2024 Reviewers invited by journal 04 May, 2024 Editor assigned by journal 26 Apr, 2024 Editor invited by journal 23 Apr, 2024 Submission checks completed at journal 23 Apr, 2024 First submitted to journal 07 Apr, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4231663","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":294412857,"identity":"235ce501-df83-4a07-a49a-4ad14d67a5d2","order_by":0,"name":"Yuki Aoyama","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Aoyama","suffix":""},{"id":294412858,"identity":"d0149824-31d9-4af2-9ae4-3eeec76b0155","order_by":1,"name":"Sakiko Hiraoka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABFElEQVRIie2RsWrDMBRFnzB4CnR1l/gLChZZCqXpr8gY4il0zRCKIWAvIV5V2o9wF80SAk+CrBo62Eu6tovHUNVZHGK3zVaKznSFdKQrCcBi+ZO4IBLg46+Iku7E8ehUmZynmDkeJt8u6uJnZSjo4jXOM45qupT+VcZdD5ZTcJ76dwjUjItC7eZUEQcXpcRMEaOUEaBn3q9AnIg6lfPCA/eyciVi/L4xmQOipL9Y/tYqcdAqe3nHtpU5ZT+sgDbFXlJJWsWEkGlTDKXDSqB3RFAlMVXhCj9u4ojpyrkON9Fo6C5+Ppt8rBfSv8ikqNfNzS3bEqTfm+kYD7xYh/ZXVodsKo0w/ck48NAp4P1OsVgsln/PJ+GFa+OWamKfAAAAAElFTkSuQmCC","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Sakiko","middleName":"","lastName":"Hiraoka","suffix":""},{"id":294412859,"identity":"af0d48ca-2cad-4975-a169-f4b1c9f72ed5","order_by":2,"name":"Eriko Yasutomi","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eriko","middleName":"","lastName":"Yasutomi","suffix":""},{"id":294412860,"identity":"0aa8f97b-71e8-4565-8f03-d8d13aec5484","order_by":3,"name":"Toshihiro Inokuchi","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Toshihiro","middleName":"","lastName":"Inokuchi","suffix":""},{"id":294412861,"identity":"5022c45f-6133-4693-acde-3dfcf2ed9190","order_by":4,"name":"Takehiro Tanaka","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takehiro","middleName":"","lastName":"Tanaka","suffix":""},{"id":294412862,"identity":"e54b6126-85fb-4c98-ad45-c9b281c58259","order_by":5,"name":"Kensuke Takei","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kensuke","middleName":"","lastName":"Takei","suffix":""},{"id":294412863,"identity":"021e884a-1699-4c59-addb-335e7911e63b","order_by":6,"name":"Shoko Igawa","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shoko","middleName":"","lastName":"Igawa","suffix":""},{"id":294412864,"identity":"8e5cd61c-f943-43ae-b37c-ff1fc47c0761","order_by":7,"name":"Keiko Takeuchi","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keiko","middleName":"","lastName":"Takeuchi","suffix":""},{"id":294412865,"identity":"84957c70-8527-4897-b1ce-b527ad9b86a7","order_by":8,"name":"Masahiro Takahara","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Takahara","suffix":""},{"id":294412866,"identity":"b90f13ec-2b28-40da-a9c4-28fa8f80783e","order_by":9,"name":"Junki Toyosawa","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Junki","middleName":"","lastName":"Toyosawa","suffix":""},{"id":294412867,"identity":"d1ff2692-730f-453d-910c-8879d0e419a3","order_by":10,"name":"Yasushi Yamasaki","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yasushi","middleName":"","lastName":"Yamasaki","suffix":""},{"id":294412868,"identity":"731915b1-ccdb-4f6e-addb-dfa53a0b5ad4","order_by":11,"name":"Hideaki Kinugasa","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hideaki","middleName":"","lastName":"Kinugasa","suffix":""},{"id":294412869,"identity":"48c8bb5f-c0e3-44dc-9774-9366f14da334","order_by":12,"name":"Jun Kato","email":"","orcid":"","institution":"Chiba University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Kato","suffix":""},{"id":294412875,"identity":"53f4d85a-9d2a-48be-a355-3e1188a8947b","order_by":13,"name":"Hiroyuki Okada","email":"","orcid":"","institution":"Japanese Red Cross Society Himeji Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Okada","suffix":""},{"id":294412877,"identity":"cad2e359-a73d-48d5-b28e-92fb0edb6e04","order_by":14,"name":"Motoyuki Otsuka","email":"","orcid":"","institution":"Okayama University Graduate School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Motoyuki","middleName":"","lastName":"Otsuka","suffix":""}],"badges":[],"createdAt":"2024-04-07 13:59:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4231663/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4231663/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-89615-8","type":"published","date":"2025-02-12T15:57:45+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":55539036,"identity":"22a91a56-7c8d-430d-8414-b13229a402e3","added_by":"auto","created_at":"2024-04-29 16:54:06","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32449,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlowchart\u003c/strong\u003e \u003cstrong\u003efor analyses of comparison between the changes in fecal/serum marker levels and the change in MES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMES: Mayo Endoscopic Subscore. The numbers of the cases with each endoscopic activity level (MES 0-3) at the precedent colonoscopy test and the numbers of cases with improved, unchanged, and worsened activity in the subsequent colonoscopy tests are indicated.\u003c/p\u003e","description":"","filename":"SRFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/dd019ca53d862fa178f91e94.png"},{"id":55539665,"identity":"9dd90e91-0b44-438f-ac99-abfee7fc6d2a","added_by":"auto","created_at":"2024-04-29 17:02:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66202,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the changes in fecal/serum marker levels and the change in MES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelation between the change in MES and the changes in Fcal (\u003cstrong\u003ea\u003c/strong\u003e), FIT (\u003cstrong\u003eb\u003c/strong\u003e), serum LRG (\u003cstrong\u003ec\u003c/strong\u003e), and serum CRP (\u003cstrong\u003ed\u003c/strong\u003e) levels. MES, Mayo Endoscopic Subscore; Fcal, fecal calprotectin; FIT, fecal immunochemical test; LRG, leucine-rich alpha 2 glycoprotein; CRP, C-reactive protein. Each Δ represents the amount of change. The line indicates the correlation coefficient between the changes of fecal/serum marker levels and the maximum MES obtained by Spearman's rank correlation. The correlation values and P-values are shown in the upper left corner.\u003c/p\u003e","description":"","filename":"SRFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/5a43c2a69556d609a2977305.png"},{"id":55539038,"identity":"1f310321-4f44-40e7-acde-30e77bd85c7c","added_by":"auto","created_at":"2024-04-29 16:54:07","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":68637,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the changes in fecal/serum marker levels and the change in the maximum Geboes score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelation between the change in the maximum Geboes score and the changes in Fcal (\u003cstrong\u003ea\u003c/strong\u003e), FIT (\u003cstrong\u003eb\u003c/strong\u003e), serum LRG (\u003cstrong\u003ec\u003c/strong\u003e), and serum CRP (\u003cstrong\u003ed\u003c/strong\u003e) levels. Fcal, fecal calprotectin; FIT, fecal immunochemical test; LRG, leucine-rich alpha 2 glycoprotein; CRP, C-reactive protein. Each Δ represents the amount of change. The line indicates the correlation coefficient between the changes of fecal/serum marker levels and maximum Geboes score obtained by Spearman's rank correlation. The correlation values and P-values are shown in the upper left corner.\u003c/p\u003e","description":"","filename":"SRFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/7bc86a4e95176889af684af5.png"},{"id":55539041,"identity":"3ce7ad54-c7be-488d-abde-a37c4778e731","added_by":"auto","created_at":"2024-04-29 16:54:07","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":65624,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the fecal/serum marker levels and maximum MES\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelation between the MES and the levels of Fcal (\u003cstrong\u003ea\u003c/strong\u003e), FIT (\u003cstrong\u003eb\u003c/strong\u003e), serum LRG (\u003cstrong\u003ec\u003c/strong\u003e), and serum CRP (\u003cstrong\u003ed\u003c/strong\u003e) at each analysis point. MES, Mayo Endoscopic Subscore; Fcal, fecal calprotectin; FIT, fecal immunochemical test; LRG, leucine-rich alpha 2 glycoprotein; CRP, C-reactive protein. The line indicates the correlation coefficient between the fecal/serum marker levels and maximum MES obtained by Spearman's rank correlation. The correlation values and P-values are shown in the upper left corner.\u003c/p\u003e","description":"","filename":"SRFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/1e186951de9cc3cf7104578a.png"},{"id":55539040,"identity":"85032fe8-b499-4429-9f80-c516c82cc1b4","added_by":"auto","created_at":"2024-04-29 16:54:07","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67648,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the fecal/serum marker levels and maximum Geboes score\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelation between the maximum Geboes score and the levels of Fcal (\u003cstrong\u003ea\u003c/strong\u003e), FIT (\u003cstrong\u003eb\u003c/strong\u003e), serum LRG (\u003cstrong\u003ec\u003c/strong\u003e), and serum CRP (\u003cstrong\u003ed\u003c/strong\u003e). Fcal, fecal calprotectin; FIT, fecal immunochemical test; LRG, leucine-rich alpha 2 glycoprotein; CRP, C-reactive protein. The line indicates the correlation coefficient between the fecal/serum marker levels and the maximum Geboes score obtained by Spearman's rank correlation. The correlation values and P-values are shown in the upper left corner.\u003c/p\u003e","description":"","filename":"SRFigure5.png","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/35bd3f9ba812be429cfcec02.png"},{"id":76488347,"identity":"2951793b-8de3-4fa3-a163-0d420fac243f","added_by":"auto","created_at":"2025-02-17 16:14:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1250147,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/5f5dc2c7-d270-4184-944d-cb4ffa4f81a7.pdf"},{"id":55539043,"identity":"ad7595d4-a7bb-4282-a67f-69b8957115ac","added_by":"auto","created_at":"2024-04-29 16:54:07","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":148871,"visible":true,"origin":"","legend":"","description":"","filename":"SRSupplementalMaterial.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4231663/v1/bed89aab932b06848fca2dd3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUlcerative colitis (UC) is a chronic, refractory inflammatory bowel disease (IBD) of unknown cause and can be diagnosed based on clinical evaluation and a combination of hematological, endoscopic, histological, or imaging-based investigations\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Clinical remission has been the primary target of treatment; however, endoscopic remission, which means that endoscopy shows no mucosal inflammation, has recently been recognized as more appropriate\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. For this purpose, endoscopic evaluation would be desirable to accurately evaluate disease activity. However, the significant physical and economic burdens make it difficult to perform frequent endoscopic examinations. As an alternative, serum and/or stool markers, such as serum C-reactive protein (CRP), fecal calprotectin (Fcal) and fecal immunochemical test (FIT), have been studied as inflammatory markers for inferring the disease activity\u003csup\u003e\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e–\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Although stool testing is useful, compliance is hampered in some patients\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e–\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. In this point, blood tests are simpler examinations for all patients than fecal tests. However, because serum CRP levels are not always informative in patients with UC\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, the monitoring of serum CRP is not adequate for assessing the disease activity of UC. Therefore, there is a strong need for new reliable serum markers for inferring the disease activity of UC.\u003c/p\u003e \u003cp\u003eSerum leucine-rich alpha 2 glycoprotein (LRG) is a substance obtained by proteomic screening from patients with rheumatoid arthritis (RA)\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Unlike CRP, LRG is induced not only by IL-6 but also by other proinflammatory cytokines\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, and is expressed not only in liver but also in local inflammatory sites, produced by neutrophils, macrophages, hepatocytes, and intestinal epithelial cell\u003csup\u003e\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e–\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Indeed, serum LRG was reported to be more strongly correlated with the disease activity of RA in comparison to serum CRP\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the case of IBD, the serum LRG levels are higher in patients with active-phase UC\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Therefore, serum LRG can be a good candidate as a novel serum marker for evaluating the disease activity of UC\u003csup\u003e\u003cspan additionalcitationids=\"CR17\" citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e, which may be clinically beneficial. However, there are a few reports that the correlation between LRG values and endoscopic/histologic activity was better than CRP, but inferior to fecal markers such as Fcal and FIT\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Therefore, the best way to use this marker to evaluate the disease activity of UC during the chronic course in the clinical setting has not been determined.\u003c/p\u003e \u003cp\u003eIn some biomarkers, because the baseline levels may differ among individuals, focusing on the changes in the levels during the course of chronic diseases may be more useful than focusing on the absolute value at one analysis point. In fact, the changes in the level of Fcal more precisely reflect the changes in endoscopic activity than those in FIT; this was revealed by focusing on the changes in values during the disease course\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Previous reports have assessed that LRG correlated with UC activity at one analysis point\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, but have not assessed the correlation between the changes in LRG levels and colonic mucosal activity including comparisons with other biomarkers. Therefore, in this study, we focused on the changes in biomarker levels between paired colonoscopy tests during the management of patients with UC, to determine how these biomarkers, including the serum LRG level, can be better used.\u003c/p\u003e "},{"header":"Methods","content":"\u003ch2\u003e1. Patients\u003c/h2\u003e\u003cp\u003eSince November 2015, we have continuously asked patients with UC who were scheduled for colonoscopy at Okayama University Hospital to provide fecal and serum samples at the same time as the colonoscopy for the purpose of analyzing correlations between biomarkers and endoscopic/histologic activity. Building on our previous study\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, this study aimed to analyze the correlation between changes in colonic mucosal activity and changes in fecal and serum marker levels between two colonoscopies. Therefore, patients who underwent two or more colonoscopies and provided samples between November 2015 and November 2021 were included. In the patients who underwent more than three colonoscopies during the study period, data between two consequent colonoscopy tests were compared.\u003c/p\u003e\u003cp\u003eThe exclusion criteria were insufficient stool collection or the failure to achieve full endoscopic observation of the patients’ lesions. Patients with other diseases that could affect the serum levels of LRG and CRP (i.e., extraintestinal complications, infectious disease, collagen disease, primary biliary cholangitis, heart failure, or malignancy) at the time of endoscopy were excluded.\u003c/p\u003e\n\u003ch3\u003e2. Assessment of the endoscopic disease activity\u003c/h3\u003e\n\u003cp\u003e Colonic mucosal activity was assessed by endoscopic disease activity and pathologic activity of tissue obtained at the time of colonoscopy. All patients in this study received bowel preparation with a polyethylene glycol-based or magnesium citrate-based electrolyte solution for colonoscopy according to the standard protocol in our hospital. According to the results of colonoscopy, disease activity was evaluated by assigning the Mayo Endoscopic Subscore (MES) to the sites with the most severe mucosal inflammation. The MES was evaluated using a four-point scale (0\u0026ndash;3). An MES 0\u0026ndash;1 was defined as endoscopic remission, while MES 2\u0026ndash;3 was defined as endoscopic active-phase disease\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Change from endoscopic remission (MES 0\u0026ndash;1) to endoscopic active-phase disease (MES 2\u0026ndash;3) was defined as endoscopic relapse. Without referring to the medical records and results of the fecal and serum markers at the time of colonoscopy, the MES was assessed by two independent endoscopy specialists.\u003c/p\u003e\n\u003ch3\u003e3. Pathologic scoring\u003c/h3\u003e\n\u003cp\u003ePathological activity was scored by gastrointestinal pathologists using the Geboes score\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The Geboes score is classified into 6 grades from grade 0 to grade 5. Histological remission is defined as Geboes score\u0026thinsp;\u0026lt;\u0026thinsp;2.1. The biopsy specimen used for the evaluation of histopathological activity was obtained from the site with maximum endoscopic activity, while for remission cases, a biopsy specimen from the rectum was analyzed. When one or more biopsy specimens were evaluated in each patient, the highest score was used for the analyses.\u003c/p\u003e\n\u003ch3\u003e4. Serum sampling and analyses\u003c/h3\u003e\n\u003cp\u003eBlood samples were collected from all patients for the determination of the serum LRG and CRP levels on the day of endoscopy. Serum samples for LRG measurement were stored at -80\u0026deg;C until use. LRG was measured in bulk later at our institution using a NANOPIA LRG kit (SEKISUI MEDICAL, Tokyo, Japan)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Serum CRP was measured at our institution using a NANOPIA CRP kit (SEKISUI MEDICAL, Tokyo, Japan) on the day of colonoscopy. The measurement range of this high-sensitivity kit was from 0.01 mg/dL to 42 mg/dL.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e5. Fecal sampling and analyses\u003c/h2\u003e \u003cp\u003ePatients were requested to prepare two fecal samples within 2 days before colonoscopy for the examination of calprotectin and FIT. Fecal samples collected by the patients were stored at \u0026minus;\u0026thinsp;30\u0026deg;C until shipment to the BML (Tokyo, Japan), where the level of calprotectin in the fecal specimen (Fcal) was measured with a fluorescence enzyme immunoassay using Phadia EliA Calprotectin 2 (Thermo Fisher Scientific, Phadia AB, Uppsala, Sweden). The FIT was performed at our institution using an OC-Sensor DIANA or PLEDIA system (Eiken Chemical, Tokyo, Japan) with stool samples collected with a Hemodia sampling probe (Eiken Chemical)\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Because the FIT is not accurate for measuring hemoglobin concentrations of \u0026lt;\u0026thinsp;50 ng/mL, the specimens with a hemoglobin concentration within this range (0\u0026ndash;50 ng/mL) were all treated as 50 ng/mL in this study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e6. Statistical Analyses\u003c/h2\u003e \u003cp\u003eThe characteristics of patients were described with numbers and percentages for categorical variables, indicating the mean standard deviation or median (range) for continuous variables according to the distribution. Spearman\u0026rsquo;s rank correlation test was used for determining the correlations between the levels of serum/fecal markers and the MES or Geboes scores. Receiver operating characteristic (ROC) analyses were used to assess the cut-off values of serum/fecal markers between the endoscopic status of MES 0\u0026ndash;1 and MES 2\u0026ndash;3 and the histological status of Geboes score\u0026thinsp;\u0026lt;\u0026thinsp;2.1 and Geboes score\u0026thinsp;\u0026ge;\u0026thinsp;2.1. The results were expressed as the area under the curve (AUC), with sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy with 95% confidence intervals. Two-sided p values of \u0026lt;\u0026thinsp;0.05 were considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e7. Ethical considerations\u003c/h2\u003e \u003cp\u003e This study was approved by the Institutional Review Board of Okayama University Graduate School of Medicine (IRB number: 1904-035) and conducted in accordance with the Declaration of Helsinki. All research was performed in accordance with the relevant guidelines/regulations. Informed consent was obtained from each patient and/or their legal guardians.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e1. Clinical characteristics of the patients\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eTwo hundred twenty-nine patients with UC were registered and 352 endoscopic examinations were performed during the observation period. Seventy-nine of the registered patients underwent colonoscopy tests more than once and provided fecal/serum samples. The characteristics of the 79 enrolled patients, the colonoscopy findings, and the values of biomarkers are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Forty male and thirty-nine female patients with a median (range) age of 48.0 years (37.5\u0026ndash;57.6 years) were included in the study. The median (range) age at the onset of the disease was 36.4 years (25.3\u0026ndash;45.2 years old), and the median (range) disease duration was 9.8 years (3.8\u0026ndash;16.8). There were 52 cases of extensive colitis (65.8%), 22 cases of left-sided colitis (27.8%), 4 cases of proctitis (5.1%), and 1 case of right-sided colitis (1.3%). For the analysis of the changes of endoscopic activity and biomarkers, the maximum MES for the colorectum, as determined based on the precedent findings of 123 paired colonoscopic, was as follows: MES 0, n\u0026thinsp;=\u0026thinsp;51 (41.4%); MES 1, n\u0026thinsp;=\u0026thinsp;35 (28.5%); MES 2, n\u0026thinsp;=\u0026thinsp;28 (22.8%); and MES 3, n\u0026thinsp;=\u0026thinsp;9 (7.3%). The interval between the two consecutive colonoscopy tests that were used for the analyses of data was 15.4 months (11.7\u0026ndash;25.6 months).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of the enrolled patients, colonoscopy findings, and biomarker values\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;79\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, n (%): male / female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (50.6)/ 39 (49.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range) age at precedent colonoscopy, years\u003c/p\u003e \u003cp\u003eMedian (range) age at the onset of the disease, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48.0 (37.5\u0026ndash;57.6)\u003c/p\u003e \u003cp\u003e36.4 (25.3\u0026ndash;45.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range) disease duration\u003c/p\u003e \u003cp\u003eat precedent colonoscopy, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.8 (3.8\u0026ndash;16.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease location, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExtensive/ Left-sided/ Proctitis/ Right-sided\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (65.8)/22 (27.8)/4 (5.1)/1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnalyzed colonoscopic pairs, 1/ 2/ 3/ 4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51/ 17/ 6/ 5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eColonoscopies (paired)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;123\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActivity assessment at the precedent colonoscopy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMayo endoscopic subscore, n (%): 0/ 1/ 2/ 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e51 (41.4)/35 (28.5)/28 (22.8)/9 (7.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e*Geboes score, n (%): 0/1/2/3/4/5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (14.0)/38 (31.4)/12 (9.9)/\u003c/p\u003e \u003cp\u003e16 (13.2)/17 (14.0)/21 (17.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eValues of biomarkers,\u003c/p\u003e \u003cp\u003emedian (range) at the precedent colonoscopy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFecal calprotectin, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e119 (31\u0026ndash;447)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFecal immunochemical test, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50 (50\u0026ndash;315)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeucine-rich alpha 2 glycoprotein, \u0026micro;g/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.6 (10.1\u0026ndash;14.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC-reactive protein, mg/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.08 (0.04\u0026ndash;0.19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian (range) interval between the precedent\u003c/p\u003e \u003cp\u003eand subsequent colonoscopy, months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.4 (11.7\u0026ndash;25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e*Two colonoscopies, no biopsies were taken.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe treatments of the 79 patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Of 123 paired cases, medication was changed between the precedent and subsequent colonoscopic examinations in 48 pairs (39.0%). Immunosuppressive medication was introduced for the 14 pairs (11.4%) and interrupted in 19 pairs (15.4%) (Supplemental Table\u0026nbsp;1).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMedication at the precedent colonoscopy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConcomitant medication at the precedent colonoscopy, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5-aminosalicylic acid, oral agent / suppository\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e67 (84.8) / 17 (21.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSteroid, oral agent / suppository\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7 (8.9) / 3 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImmunomodulator\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35 (44.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnti-tumor necrosis factor-α agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9 (11.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVedolizumab\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (3.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJanus kinase inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1 (1.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTacrolimus\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4 (5.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndigo naturalis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5 (6.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2. Correlation between the changes in the MES and biomarker levels\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe changes in the endoscopic activity scores in 123 intervals from the consecutive colonoscopic examination are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. During the intervals of the two consecutive examinations, 29 showed improved MES values, 63 showed unchanged MES values, and 31 showed worsened MES values (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe changes of the fecal and serum marker levels in the improved, unchanged, and worsened groups, respectively, were as follows: Fcal. -167 (-1054\u0026ndash;0) \u0026micro;g/g, 0 (0\u0026ndash;64.5) \u0026micro;g/g, 69 (0\u0026ndash;766.5) \u0026micro;g/g; FIT, -150.4 (-911 - -13.7) ng/mL, -10.9 (-112.6\u0026ndash;64.0) ng/mL, 158.9 (-20.0\u0026ndash;1132) ng/mL; LRG, -2.1 (-5.1 - -0.11) \u0026micro;g/mL, -0.08 (-1.4\u0026ndash;2.2) \u0026micro;g/mL, 1.5 (0.28\u0026ndash;5.4) \u0026micro;g/mL; and CRP, -0.035 (-0.18\u0026ndash;0.038) mg/dL, 0.005 (-0.038\u0026ndash;0.07) mg/dL, 0.01 (-0.02\u0026ndash;0.07) mg/dL. Spearman\u0026rsquo;s rank correlations between the changes of MES and the changes of fecal/serum marker levels were as follows; Fcal, r\u0026thinsp;=\u0026thinsp;0.50, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; FIT, r\u0026thinsp;=\u0026thinsp;0.41, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; LRG, r\u0026thinsp;=\u0026thinsp;0.42, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; and CRP, r\u0026thinsp;=\u0026thinsp;0.22, p\u0026thinsp;=\u0026thinsp;0.013 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)༎These results suggested that the changes in LRG were significantly more strongly correlated with the changes in endoscopic activity than the changes in CRP levels. In addition, the cut-off values of change of each biomarker for endoscopic relapse were examined based on 86 cases of MES 0\u0026ndash;1 at the first colonoscopy. Of these, 66 cases remained MES 0\u0026ndash;1, while 20 cases showed relapse (MES 2\u0026ndash;3) at the second colonoscopy. The cut-off values for fecal and serum markers were shown the supplemental material (Supplemental Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3. Correlation between the changes in Geboes score and the changes in biomarker levels\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eBecause no biopsy specimens were obtained in 2 colonoscopy tests, 121 paired cases were analyzed pathologically. Among 121 cases, 45 paired cases showed improved Geboes scores (ΔGeboes score: -4, n\u0026thinsp;=\u0026thinsp;5; -3, n\u0026thinsp;=\u0026thinsp;7; -2, n\u0026thinsp;=\u0026thinsp;11; -1, n\u0026thinsp;=\u0026thinsp;22), 36 showed unchanged scores: (ΔGeboes score 0), and 40 showed worsened Geboes scores (ΔGeboes score: 1, n\u0026thinsp;=\u0026thinsp;13; 2, n\u0026thinsp;=\u0026thinsp;13; 3, n\u0026thinsp;=\u0026thinsp;9; 4, n\u0026thinsp;=\u0026thinsp;5).\u003c/p\u003e \u003cp\u003eThe changes in the fecal/serum markers of the improved, unchanged, and worsened groups, respectively, were as follows: Fcal, -99 (-249\u0026ndash;1.0) \u0026micro;g/g, -27 (-148\u0026ndash;26) \u0026micro;g/g, 114 (3.0\u0026ndash;784) \u0026micro;g/g; FIT, 0 (-828\u0026ndash;0) ng/mL, 0 (0\u0026ndash;15) ng/mL, 28 (0\u0026ndash;785) ng/mL; LRG, -1.0 (-5.0\u0026ndash;0.23) \u0026micro;g/mL, -0.11 (-1.93\u0026ndash;2.16) \u0026micro;g/mL, 1.45 (0.08\u0026ndash;4.53) \u0026micro;g/mL; and CRP, -0.01 (-0.08\u0026ndash;0.04) mg/dL, 0 (-0.09\u0026ndash;0.06) mg/dL, 0.02 (-0.02\u0026ndash;0.09) mg/dL.\u003c/p\u003e \u003cp\u003eSpearman\u0026rsquo;s rank correlations between the changes in the Geboes score and the changes in fecal/serum marker levels were as follows: Fcal, r\u0026thinsp;=\u0026thinsp;0.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; FIT, r\u0026thinsp;=\u0026thinsp;0.40, p\u0026thinsp;=\u0026thinsp;0.028; LRG, r\u0026thinsp;=\u0026thinsp;0.40, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; CRP, r\u0026thinsp;=\u0026thinsp;0.17, p\u0026thinsp;=\u0026thinsp;0.06 (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). These results suggested that the changes in LRG were similarly correlated with the fecal markers and significantly more strongly correlated with the changes in histological activity than those in CRP levels.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4. Correlation between the MES and the fecal/serum marker levels at 202 time points\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe correlation between the MES and each biomarker level at 202 time points in 123 paired cases is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. One hundred fifty-two (75.2%) of 202 colonoscopies showed no or mild endoscopic activity (MES 0 or 1). Spearman\u0026rsquo;s rank correlations between the MES and the fecal/serum marker levels were as follows: Fcal, r\u0026thinsp;=\u0026thinsp;0.53, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; FIT, r\u0026thinsp;=\u0026thinsp;0.62, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; LRG, r\u0026thinsp;=\u0026thinsp;0.32, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; and CRP, r\u0026thinsp;=\u0026thinsp;0.25, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001. The detectability of endoscopic remission (MES 0\u0026ndash;1) in the ROC analysis is also shown (Supplemental Table\u0026nbsp;3). The cut-off values of LRG for endoscopic remission (MES 0\u0026ndash;1) was 14.8 \u0026micro;g/mL. These results suggested that fecal marker levels were more strongly correlated with the endoscopic activity than the serum markers at a single time point of measurement and had higher diagnostic rates, especially in determining endoscopic remission.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e5. Correlation between the Geboes score and the fecal/serum marker levels at 202 time points\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003eThe correlations between the Geboes score and each biomarker level at 202 time points in 123 paired cases is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. Spearman\u0026rsquo;s rank correlations between the Geboes score and the fecal/serum marker levels were as follows: Fcal, r\u0026thinsp;=\u0026thinsp;0.40, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; FIT, r\u0026thinsp;=\u0026thinsp;0.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; LRG, r\u0026thinsp;=\u0026thinsp;0.34, p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; and CRP, r\u0026thinsp;=\u0026thinsp;0.18, p\u0026thinsp;=\u0026thinsp;0.0094. The detectability of histological remission (Geboes score\u0026thinsp;\u0026lt;\u0026thinsp;2.1) in the ROC analysis of each biomarker is shown in Supplemental Table\u0026nbsp;4. The cut-off value of LRG for histological remission (Geboes score\u0026thinsp;\u0026lt;\u0026thinsp;2.1) was 12.6 \u0026micro;g/mL. These results suggested that LRG was more strongly correlated with the histological activity than CRP.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eOur study showed that the changes in serum LRG between two consecutive colonoscopy tests were significantly correlated with the changes in the endoscopic and histologic activity, when presently available serum biomarkers are not sufficiently effective for monitoring the disease activity. To our knowledge, our results are unique in real-world clinical practice, in the point of view that comparing the changes in the serum LRG/CRP levels and the Fcal/FIT levels with the changes in the endoscopic and histologic scores in the same UC patient.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003edetermined the correlation between serum LRG and the disease activity of UC using single-point analyses\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In addition, the comparison of the biomarkers including LRG with findings of multiple endoscopies has already been reported and discussed in a previous well-conceived prospective report\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. In contrast to the previous studies, our report has the following advantages. First, most of our patients were in remission or mild disease in outpatient settings that enabled validation of usefulness of LRG in real clinical practice with not so large changes in disease activity. Second, all analyzed biomarkers including FIT, which was clinically useful but was not examined in the previous reports, were compared to the endoscopic and histologic findings. The results that the changes in the serum LRG had a strong correlation in with the trend in UC activity, similarly to fecal markers, are meaningful for daily clinical practice.\u003c/p\u003e \u003cp\u003eBased on the above results, we propose the following usage of each biomarker in clinical practice related to UC. In cases with high activity (MES2-3) during the induction period, CRP has been reported to be more strongly correlated with the MES in comparison to fecal markers\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. The heterogeneity in fecal samples in cases of diarrhea due to excessive disease activity may make measurements inaccurate. In these situations, however, LRG could be useful because CRP are likely to be negative during remission induction despite residual endoscopic activity.\u003c/p\u003e \u003cp\u003eIn cases with low disease activity (MES 1), such as those with mild inflammation without clinical symptoms, serum CRP levels are often negative and are not useful\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. On the other hand, Fcal and FIT may be significantly correlated with the change from low disease activity to remission (MES 0\u0026ndash;1)\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Based on the present study, the examination of serum LRG may also be useful for these cases. Especially when fecal markers do not show any significant decrease despite appropriate therapeutic intervention, the combined use of the changes in serum LRG with fecal markers may be useful because fecal markers yield false positive results due to the use of non-steroidal anti-inflammatory drugs, the presence of hemorrhoids, inflammatory polyps, colonic diverticulum, the infection with bacteria or viruses, the diurnal variation, or menstruation in women\u003csup\u003e\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29\" citationid=\"CR26\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. In determining endoscopic remission (MES 0) and assessing the maintenance of MES 0, fecal markers may be more useful than serum LRG\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. However, once fecal markers become elevated with or without symptom relapse, the examination of changes in serum LRG may be useful for assessing the changes in disease activity.\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eThe present study was associated with several limitations. First, since this was a single-center study, confirmation by multi-center studies is desirable. Second, the population was biased toward patients with relatively low inflammation (MES 0\u0026ndash;1). Similar studies should be conducted that include cases with high inflammation (MES 2\u0026ndash;3). Third, the intervals of colonoscopy and biomarker examinations were not fixed and different among individuals. Fourth, all cases with fecal hemoglobin concentrations of \u0026lt;\u0026thinsp;50 ng/mL were treated as 50 ng/mL in this study. More accurate data may be necessary for patients with hemoglobin concentrations of \u0026lt;\u0026thinsp;50 ng/mL.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e \u003cp\u003eIn conclusion, the examination of the changes in serum LRG may be more useful and accurate than serum CRP for assessing the changes of UC disease activity, and shows similar clinical significance to the examination of fecal markers. Measurement of serum LRG can be performed by simple blood collection. Hence, LRG may have utility in the management of the chronic course of UC.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eulcerative colitis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIBD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einflammatory bowel disease\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFcal\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efecal calprotectin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIT\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003efecal immunochemical test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLRG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eleucine-rich alpha 2 glycoprotein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erheumatoid arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMayo endoscopic subscore\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eROC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eReceiver Operating Characteristic\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eAUC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003earea under the curve\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epositive predictive value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003enegative predictive value.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflicts of Interest: \u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#20K12669 to S.H. and #22H02828 to M.O.).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eConceptualization: S.H.; Methodology: Y.A., S.H.; Formal analysis and investigation: Y. A., S.H., Y.Y.; Writing - original draft preparation: Y.A., S.H.; Writing - review and editing: Y.A., S.H., T.I., T.T., K.Takei., S.I., K.Takeuchi., M.T., J.T., H.K.; Resources: Y. A., E.Y.; Supervision: H.O., J.K., M.O. All authors have read and approved the final version to be published.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe would like to thank Mr. Masanori Furukawa for their efforts in measuring serum LRG samples. We are also thankful to Ms. Mayumi Tokumitsu for her invaluable help in data input.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003e The data underlying this article will be shared on reasonable request to the corresponding author and it is provided within the manuscript or supplementary information files.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMowat C, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. 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Clin Gastroenterol Hepatol \u003cstrong\u003e12\u003c/strong\u003e, 2567-2576 (2021).\u003c/li\u003e\n\u003cli\u003eYoshimura T, Mitsuyama K, Sakemi R, Takedatsu H, Yoshioka S, et al. Evaluation of Serum Leucine-Rich Alpha-2 Glycoprotein as a New Inflammatory Biomarker of Inflammatory Bowel Disease. Mediators Inflamm \u003cstrong\u003e2021\u003c/strong\u003e, 8825374 (2021).\u003c/li\u003e\n\u003cli\u003eIshida N, Higuchi T, Miyazu T, Tamura S, Tani S, et al. C-reactive protein is superior to fecal biomarkers for evaluating colon-wide active inflammation in ulcerative colitis. Sci Rep \u003cstrong\u003e11\u003c/strong\u003e, 12431 (2021).\u003c/li\u003e\n\u003cli\u003eSonoyama H, Kawashima K, Ishihara S, Kotani S, Fukuba N, et al. Capabilities of fecal calprotectin and blood biomarkers as surrogate endoscopic markers according to ulcerative colitis disease type. J Clin Biochem Nutr \u003cstrong\u003e64\u003c/strong\u003e, 265-270 (2019).\u003c/li\u003e\n\u003cli\u003eLasson A, Stotzer PO, Ohman L, Isaksson S, Sapnara M, et al. The intraindividual variability of faecal calprotectin : a prospective study in patients with active ulcerative colitis. J Crohns Colitis \u003cstrong\u003e9\u003c/strong\u003e, 26-32 (2015).\u003c/li\u003e\n\u003cli\u003eHusebye E, Ton H, Johne B. Biological variability of fecal calprotectin in patients referred for colonoscopy without colonic inflammation or neoplasm. Am J Gastroenterol \u003cstrong\u003e96\u003c/strong\u003e, 2683-2687 (2001).\u003c/li\u003e\n\u003cli\u003eCalafat M, Cabr\u0026eacute; E, Ma\u0026ntilde;osa M, Lobat\u0026oacute;n T, Mar\u0026iacute;n L, et al. High within-day variability of fecal calprotectin levels in patients with active ulcerative colitis: what is the best timing for stool sampling? Inflamm Bowel Dis \u003cstrong\u003e21\u003c/strong\u003e, 1072-1076 (2015). \u003c/li\u003e\n\u003cli\u003evan Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ \u003cstrong\u003e341\u003c/strong\u003e, c3369 (2010). \u003c/li\u003e\n\u003cli\u003eFagerberg UL, L\u0026ouml;\u0026ouml;f L, Merzoug RD, Hansson LO, Finkel Y. Fecal calprotectin levels in healthy children studied with an improved assay. J Pediatr Gastroenterol Nutr \u003cstrong\u003e37\u003c/strong\u003e, 468-472 (2003).\u003c/li\u003e\n\u003cli\u003eVan Turenhout ST, Oort FA, Terhaar sive Droste JS, Coup\u0026eacute; VM, van der Hulst RW, et al. Hemorrhoids detected at colonoscopy: an infrequent cause of false-positive fecal immunochemical test results. Gastrointest Endosc \u003cstrong\u003e76\u003c/strong\u003e, 136-143 (2012).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Ulcerative colitis, Leucine-rich alpha 2 glycoprotein, Biomarker","lastPublishedDoi":"10.21203/rs.3.rs-4231663/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4231663/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLeucine-rich alpha 2 glycoprotein (LRG) is one of the promising serum biomarkers for disease activity of ulcerative colitis (UC). However, several previous reports suggested that the correlation of absolute values of LRG with endoscopic/histologic activity was superior to that of CRP but inferior to those of fecal markers. Here, we focused on the correlation between the changes of LRG and the changes of endoscopic and histologic activity of UC, in comparison to the changes of fecal calprotectin (Fcal), fecal immunochemical test (FIT), and C-reactive protein (CRP). Patients with UC who underwent two or more colonoscopies were enrolled. The comparison of the changes in marker levels with the change of endoscopic/histologic activity in 123 paired colonoscopies of 79 patients revealed that the strength of the correlation in LRG (r\u0026thinsp;=\u0026thinsp;0.42/0.40) was almost similar to that of fecal markers (Fcal; r\u0026thinsp;=\u0026thinsp;0.50/0.39 and FIT; r\u0026thinsp;=\u0026thinsp;0.41/0.40) and better than that of CRP (r\u0026thinsp;=\u0026thinsp;0.22/0.17). LRG is equivalent to fecal markers and superior to CRP, when inferring changes in disease activity of UC based on changes in its level.\u003c/p\u003e","manuscriptTitle":"Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-29 16:54:02","doi":"10.21203/rs.3.rs-4231663/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-11-13T08:33:51+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-10-24T15:06:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96743113345387955889252513646718786203","date":"2024-10-09T14:46:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"203057335005643237587696357287372400902","date":"2024-08-26T09:11:01+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"326191893796327189684414366781626879269","date":"2024-07-20T19:44:47+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-06-30T08:37:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"165392191909563404063288413063693335581","date":"2024-06-24T05:58:06+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-05-04T13:38:17+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-04-26T13:01:54+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-04-23T07:23:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-04-23T07:20:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-04-07T13:47:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"77c9c112-8c0f-409c-b483-7cf4e6c8d2b0","owner":[],"postedDate":"April 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":31033492,"name":"Health sciences/Biomarkers/Predictive markers"},{"id":31033493,"name":"Health sciences/Biomarkers/Prognostic markers"},{"id":31033494,"name":"Health sciences/Gastroenterology/Colonoscopy"},{"id":31033495,"name":"Health sciences/Gastroenterology/Gastrointestinal diseases"}],"tags":[],"updatedAt":"2025-02-17T16:11:05+00:00","versionOfRecord":{"articleIdentity":"rs-4231663","link":"https://doi.org/10.1038/s41598-025-89615-8","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-02-12 15:57:45","publishedOnDateReadable":"February 12th, 2025"},"versionCreatedAt":"2024-04-29 16:54:02","video":"","vorDoi":"10.1038/s41598-025-89615-8","vorDoiUrl":"https://doi.org/10.1038/s41598-025-89615-8","workflowStages":[]},"version":"v1","identity":"rs-4231663","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4231663","identity":"rs-4231663","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}