Comparison of changes in biomarkers with changes in endoscopic scores in patients with ulcerative colitis: a single-center, retrospective, observational study

Comparison of changes in biomarkers with changes in endoscopic scores in patients with ulcerative colitis: a single-center, retrospective, observational study | 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 Research Article Comparison of changes in biomarkers with changes in endoscopic scores in patients with ulcerative colitis: a single-center, retrospective, observational study Yosuke Yamada, Natsuki Ishida, Tomohiro Takebe, Kenichi Takahashi, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8241807/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Fecal occult blood concentration, fecal calprotectin (FC) level, serum C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) are valuable biomarkers for ulcerative colitis (UC); however, their clinical utility for longitudinal disease assessment requires further clarification. This retrospective, observational study aimed to assess the correlations among changes in the values of these biomarkers and endoscopic activity scores in patients with UC. Methods We examined the relationship between longitudinal variations in endoscopic activity scores, including the Mayo endoscopic subscore (MES), ulcerative colitis endoscopic index of severity (UCEIS), and sum of Mayo endoscopic subscores (S-MES), and corresponding changes in biomarker values within the same cohort of patients with UC using Spearman's rank correlation coefficient analysis. Results All endoscopic scores and biomarkers were significantly correlated with disease activity, with corresponding increases or decreases (P < 0.05). Changes in the MES had the strongest correlation with changes in FC level (r = 0.62). The changes in the UCEIS had the strongest correlation with changes in fecal occult blood concentration (r = 0.67). Changes in S-MES had the strongest correlation with changes in FC level (r = 0.66). Changes in fecal occult blood concentration and FC level were strongly correlated (r = 0.55), as were changes in serum CRP level and ESR (r = 0.58). Conclusions All four biomarkers reflected endoscopic activity in UC; however, changes in fecal occult blood concentration and FC level had stronger correlations with changes in endoscopic scores than changes in blood biomarker values. FC level assessment is valuable for monitoring inflammatory activity during remission maintenance, whereas fecal occult blood concentration accurately reflects mucosal bleeding. Serum CRP level and ESR are useful adjunctive biomarkers, particularly in cases of increased disease activity. ulcerative colitis biomarker fecal immunochemical occult blood test fecal calprotectin Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Ulcerative colitis (UC) is a chronic inflammatory condition that usually follows a remitting-relapsing course, with symptoms such as diarrhea, rectal bleeding, and abdominal pain [ 1 , 2 ]. Accurate assessment of disease activity is essential in patients with UC to improve disease management and prognosis [ 3 ]. Assessment of disease activity has traditionally relied on clinical symptoms; however, colonoscopy (CS) is the gold standard assessment. Achieving mucosal healing (MH) is associated with decreased hospitalizations and resections, as well as reduced incidence of colorectal cancer in patients with UC [ 4 ]. Furthermore, MH induces sustained clinical remission [ 5 ]. CS is invasive, expensive, time-consuming, and associated with a risk of complications [ 5 , 6 ]. Therefore, performing CS frequently for routine monitoring is difficult. Accordingly, reliable, non-invasive biomarkers that precisely reflect intestinal inflammation and predict MH are essential. Several non-invasive assessments of biomarkers have been used to evaluate disease activity in patients with UC. Although serum C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) assessments are simple and provide immediate results, they can only indicate systemic inflammatory responses and do not directly reflect endoscopic damage to the colonic mucosa [ 7 ]. Fecal calprotectin (FC) levels have been reported to significantly correlate with endoscopic disease activity in patients with UC [ 8 ]. FC levels increase with gut inflammation, characterized by extensive mucosal infiltration by neutrophils [ 9 ], and predict clinical recurrence of disease activity in patients with UC [ 10 ]. Occult intestinal bleeding is an important clinical sign of UC, and several studies have demonstrated that fecal occult blood concentration, assessed using the fecal immunochemical occult blood test (FIT), correlate well with the severity of endoscopic inflammation [ 11 , 12 ]. Furthermore, comparative studies of biomarkers have reported that fecal occult blood concentration and FC level have stronger correlations with the Mayo Endoscopy subscore (MES) than serum CRP level [ 11 ]. Previous reports have indicated that FC level is significantly correlated with endoscopic scores regardless of the disease type (proctitis, left-sided colitis, and extensive colitis), whereas blood biomarkers, such as serum CRP level and ESR, show weak or no correlations, particularly in patients with proctitis [ 13 ]. However, the correlations of these biomarkers vary depending on the stage of disease. For example, according to Ishida et al., during the MH phase (MES: 0, 1), FC level and fecal occult blood concentration had stronger correlations with the total colonic inflammation score than serum CRP level. In contrast, during the endoscopic active phase (MES: 2, 3), serum CRP level correlated significantly stronger with the total colonic inflammation score than FC level and fecal occult blood concentration [ 14 ]. Thus, diverse findings have been reported regarding the ability of each biomarker to reflect different levels of disease activity or specific inflammatory characteristics of UC. Only one study had compared variations in fecal occult blood concentration, FC level, serum CRP level, and ESR with endoscopic activity in patients with UC [ 15 ]. In the present study, we aimed to assess the usefulness of FC level, fecal occult blood concentration, serum CRP level, and ESR in predicting disease activity in patients with UC by comparing changes in the values of these biomarkers and endoscopic scores obtained using CS performed for the entire colon. Methods 2.1. Patients and study design This study included 97 patients with UC who underwent CS at Hamamatsu University School of Medicine between January 2019 and December 2024. Three CS records (comprising two intervals) per patient were assessed in 48 patients, and two CS records (comprising one interval) per patient were assessed in the remaining 49 patients. In total, 145 intervals were assessed. UC was diagnosed according to currently established criteria based on typical clinical symptoms, endoscopic findings, and histological evaluation [ 16 ]. Patients diagnosed with indeterminate colitis or unclassified inflammatory bowel disease were excluded. Determining the sum of Mayo Endoscopy subscores (S-MES) requires observation of the entire colon; therefore, patients with UC who had undergone prior colorectal surgery were excluded. Furthermore, patients with acute infectious enteritis or those regularly taking aspirin and/or other non-steroidal anti-inflammatory drugs were excluded. The patients included in the study underwent CS for routine follow-up or clinical recurrence of UC. Endoscopic scores, including the MES, S-MES, and ulcerative colitis endoscopic index of severity (UCEIS), were assessed. This retrospective observational study aimed to longitudinally assess whether variations in FC level, fecal occult blood concentration, serum CRP level, and ESR corresponded to changes in the three distinct endoscopic scores among patients with UC. The primary endpoint was whether the four biomarker values significantly increased or decreased in response to changes in endoscopic scores during two measurements over time. The secondary endpoint was to evaluate which of the four biomarkers correlated strongly with changes in endoscopic scores. 2.2. Disease assessment Patients with UC underwent bowel preparation before CS using a polyethylene glycol-based electrolyte solution taken orally. UC endoscopic measurements included the MES, S-MES, and UCEIS. An MES of 0 indicated normal or inactive disease; 1 indicated mild disease with erythema, decreased vascular pattern, and mild friability; 2 indicated moderate disease with marked erythema, absence of vascular patterns, friability, and erosions; and 3 indicated severe disease with spontaneous bleeding and ulceration in the lesion with the most severe inflammation [ 17 ]. The S-MES was calculated as the sum of the MESs of five colonic segments (ascending, transverse, descending, sigmoid, and rectum), as described above [ 18 ]. The UCEIS was calculated as the sum of three descriptors: vascular pattern (score, 0–2), erosions and ulcers (score, 0–3), and bleeding (score, 0–3) [ 19 ]. An MES of 0 or 1 was considered indicative of MH. 2.3. Fecal calprotectin and fecal occult blood concentration measurements To avoid the effects of bleeding related to endoscopy, stool samples were collected on or before the day of the CS. Specimens for both FC assessment and FIT were obtained from the same stool sample. Samples were collected in plastic tubes for FC measurement and shipped at − 20°C, as recommended by the laboratory (SRL, Inc., Tokyo, Japan). FC level was measured using Phadia 250 immunoanalyzer (HITACHI Ltd., Tokyo, Japan) and Elia A Calprotectin 2 reagent (Phadia GmbH, Freiburg, Germany), according to fluorescence enzyme immunoassay principles. An FIT collection kit (Eiken Chemical, Tokyo, Japan) was used to collect stool specimens. The samples were immediately processed and examined using OC-SENSOR® io (Eiken Chemical). 2.4. Serum C-reactive protein level and erythrocyte sedimentation rate measurements Serum CRP level and ESR were measured to assess UC activity, according to routine clinical practice. Blood samples were collected within a few days of the endoscopic examination. These measurements were performed at the Laboratory Test Department of Hamamatsu University School of Medicine. 2.5. Statistical analysis Statistical analyses were performed using SPSS v24 (IBM Corp., Armonk, NY, USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) software [ 20 ]. Spearman's rank correlation coefficient analysis was used to evaluate the correlations among changes in the values of four biomarkers and changes in the three endoscopic scores for the preceding and subsequent CS. Statistical significance was set at P < 0.05. 2.6. Ethical statement The study protocol was reviewed and approved by the ethics committee of Hamamatsu University School of Medicine (number 24-021) before the commencement of the research. All procedures involving human participants were performed according to the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained via an opt-out method, and the study details were posted on the hospital’s website. Results 3.1. Patient characteristics The characteristics of the patients with UC at the time of first CS (N = 145) are shown in Table 1. The median patient age was 48.0 (interquartile range[IQR], 39.0–61.0) years, and the median disease duration was 8.0 (IQR, 3.0–15.0) years. The median FC and fecal occult blood levels were 398.0 μg/g and 30 ng/mL, respectively. The median serum CRP level and ESR were 0.07 mg/dL and 7.0 mm/h, respectively. Table 1. Patient characteristics Characteristics at the precedent CS Value (N = 145) Age (years), median (IQR) 48.0 (39.0–61.0) Male/Female, n (%) 101 (69.7)/44 (30.3) Disease duration (years), median (IQR) 8.0 (3.0–15.0) Disease extent, n (%) Extensive colitis 91（62.8） Left-sided colitis 39（26.9） Proctitis 15（10.3） CAI (Rachmilewitz index), median (IQR) 1 (0–3) MES, median (IQR) 1 (0–2) S-MES, median (IQR) 1 (0–3) UCEIS, median (IQR) 1 (0–3) FC level (µg/g), median (IQR) 398.0 (76.9–1810.0) Fecal occult blood concentration (ng/mL), median (IQR) 30 (30–853) Serum CRP level (mg/dL), median (IQR) 0.07 (0.03–0.15) ESR (mm/h), median (IQR) 7.0 (3–14) Medications during the study, n (%) Oral 5‒ASA 100（70.0） Suppository 5‒ASA 13（9.0） Systemic steroids 17（11.7） Immunomodulators 44（30.3） Biologics 56（38.6） CS, colonoscopy; IQR, interquartile range; CAI, clinical activity index; MES, Mayo endoscopic subscore; S-MES, sum of Mayo endoscopic subscores; UCEIS, ulcerative colitis endoscopic index of severity; FC, fecal calprotectin; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; 5-ASA, 5-aminosalicylic acid 3.2. Correlations among the biomarkers and endoscopic scores Correlations between each of the four biomarkers and each of the three endoscopic scores were analyzed (Table 2). The values of the four biomarkers significantly increased and decreased in the MES-increase and MES-decrease subgroups, respectively; no significant change was observed in the MES-no change subgroup. The values of the four biomarkers significantly increased and decreased in the UCEIS-increase and UCEIS-decrease subgroups, respectively; no significant change was observed in the UCEIS-no change subgroup. The values of the four biomarkers significantly increased and decreased in the S-MES-increase and S-MES-decrease subgroups, respectively; no significant change was observed in the S-MES-no change subgroup. [Insert Table 2 here] 3.3. Correlations among variations in Mayo Endoscopy Scores and four biomarkers Figure 1 shows the correlations among a change in the MES (ΔMES) and changes in FIT result (ΔFIT), FC level (ΔFC), serum CRP level (ΔCRP), and ESR (ΔESR) from the precedent to the subsequent CS. Significant correlations were observed among ΔMES and changes in the four biomarkers (Fig. 1A-D). However, the correlation between ΔMES and ΔFC (r = 0.62) was stronger than that among ΔMES and changes in other biomarkers (ΔFIT, r = 0.57; ΔCRP, r = 0.33; ΔESR, r = 0.40). Figure 2 shows the correlations among a change in the UCEIS (ΔUCEIS) and ΔFIT, ΔFC, ΔCRP, and ΔESR from the precedent to the subsequent CS. Significant correlations were observed among ΔUCEIS and changes in the four biomarkers (Fig. 2A-D). However, the correlation between ΔUCEIS and ΔFIT was stronger (r = 0.67) than that among ΔUCEIS and changes in the other biomarkers (ΔFC, r = 0.65; ΔCRP, r = 0.42; ΔESR, r = 0.46). We further examined the correlations of ΔFIT and ΔFC with changes in the UCEIS; changes in vascular pattern (ΔV), bleeding (ΔB), and erosions and ulcers (ΔE) were significantly correlated with both ΔFIT and ΔFC (Table 3). The correlation coefficient with ΔV was greater for ΔFC than for ΔFIT. In contrast, the correlation coefficients with ΔB and ΔE were greater for ΔFIT than for ΔFC. Figure 3 shows the correlations among a change in the S-MES (ΔS-MES) and ΔFIT, ΔFC, ΔCRP, and ΔESR from the precedent to the subsequent CS. Significant correlations were observed among ΔS-MES and changes in the four biomarkers (Fig. 3A-D). However, the correlation between ΔS-MES and ΔFC (r = 0.66) was stronger than that among ΔS-MES and changes in other biomarkers (ΔFIT, r = 0.54; ΔCRP, r = 0.39; ΔESR, r = 0.35). A significant correlation was observed between ΔFIT and ΔFC (r = 0.55; P < 0.001; Fig. 4A) and between ΔCRP and ΔESR (r = 0.58; P < 0.001; Fig. 4B). Table 3. Correlations among changes in fecal biomarker values and ulcerative colitis endoscopic index of severity parameters Variable ΔFIT ΔFC r P-value r P-value ΔUCEIS ΔV 0.57 < 0.001 0.61 < 0.001 ΔB 0.55 < 0.001 0.42 < 0.001 ΔE 0.60 < 0.001 0.57 < 0.001 ΔFIT, change in the fecal immunochemical occult blood test result; ΔFC, change in the fecal calprotectin level; r, correlation coefficient; ΔUCEIS, change in the ulcerative colitis endoscopic index of severity; ΔV, change in vascular pattern; ΔB, change in bleeding; ΔE, change in erosions and ulcers Discussion Most studies on endoscopic activity and biomarkers of UC to date have been cross-sectional, with very few longitudinal observational studies examining correlations among endoscopic scores and biomarkers [6, 21, 22]. Hiraoka et al. investigated changes in the MES between the MH and active phases in the same patients using FC level assessment and FIT. They reported that fecal occult blood concentration more accurately mirrored changes during the MH phase than FC level, whereas FC level more reliably reflected alterations during the active phase than fecal occult blood concentration [6]. However, they did not assess the correlations among the UCEIS, S-MES, FC level, and fecal occult blood concentration. Ishida et al. compared changes in the MES and S-MES with changes in prostaglandin E-major urinary metabolite (PG-MUM) and serum CRP levels in the same patients, and reported that PG-MUM reflected endoscopic scores better than serum CRP levels [21]. However, they did not assess the UCEIS and fecal occult blood concentration in relation to bleeding. Aoyama et al. further explored correlations among changes in leucine-rich alpha-2 glycoprotein (LRG), FC level, fecal occult blood concentration, and serum CRP level and alterations in the MES and UCEIS, along with assessments of histological inflammation. They observed that the correlation coefficient between ΔFC and ΔMES was greater than that between ΔFIT and ΔMES [22], a finding consistent with the present results. They did not assess changes in the total colonoscopy score. The present study is unique for its longitudinal evaluation of correlations among changes in endoscopic disease activity in UC and temporal variations in the values of the four biomarkers (fecal occult blood concentration, FC level, serum CRP level, and ESR) within the same patient cohort. Moreover, the concurrent comparisons of multiple endoscopic scores proved invaluable for identifying the distinct characteristics of each biomarker. The MES assessment is simple and easy to use in daily clinical practice and is widely used in clinical trials; however, the results show relatively high interobserver variability [23]. The UCEIS is more detailed, objective, and sensitive in reflecting changes in cases of moderate-to-severe inflammation than the MES. It also includes bleeding scores [24]. Another innovative aspect of the present study was the assessment of changes in the S-MES for the entire colon, in conjunction with alterations in fecal biomarkers. Calculation of the S-MES is time-consuming; however, it allows simultaneous assessment of the extent and severity of inflammation, enabling an accurate evaluation of the overall disease state, and is useful for determining treatment efficacy [18]. In the present study, we first examined changes in each biomarker value based on increases, decreases, or no change in the endoscopic scores. Each biomarker value was significantly elevated or reduced, corresponding to increases or decreases in the endoscopic scores. In the absence of changes in the endoscopic scores, the biomarker values did not show any significant variation. Although each biomarker demonstrated utility, we analyzed correlations among changes in biomarker values and changes in endoscopic scores to verify subtle changes. Changes in both fecal occult blood concentration and FC level significantly correlated with changes in endoscopic scores; however, each biomarker reflected distinct endoscopic characteristics. ΔFC showed the strongest correlation with both ΔMES and ΔS-MES, thereby precisely reflecting the extent and severity of inflammation. FC is a neutrophil-derived protein that accurately reflects the extent and intensity of inflammation. Consequently, FC level is strongly correlated with high disease activity. Sonoyama et al. demonstrated that FC level was significantly correlated with endoscopic activity across all disease subgroups, with particularly strong associations observed in cases of left-sided colitis (r = 0.75) and extensive colitis (r = 0.78) [14]. This report supports the results of the present correlation analysis between FC level and the S-MES. On the other hand, fecal occult blood concentration demonstrated the strongest correlation with the UCEIS and a stronger correlation with ΔE and ΔB than FC level, indicating that it primarily reflects bleeding and superficial mucosal injury rather than the underlying inflammatory process. The correlation coefficient between ΔFIT and ΔB was greater than that between ΔFC and ΔB. Sakuraba et al. reported that fecal occult blood concentration reflects endoscopic activity better than FC level in cases of UC with proctitis [25]. The reason for this may be the short retention time of stool, owing to the short distance between the site of inflammation and the anus, and the absence of diarrhea in patients with proctitis. Blood and mucus adhering to the stool surface may cause variability in FC level measurements. Therefore, fecal occult blood concentration is regarded as superior to FC level for evaluating proctitis and active disease states characterized by bleeding, whereas FC level is more effective than fecal occult blood concentration for assessing the overall intensity of inflammation. The combined use of these biomarkers may facilitate a comprehensive and multidimensional evaluation of UC disease activity. Serum CRP level and ESR also correlated with the endoscopic scores; however, their correlation coefficients were lower than those of fecal occult blood concentration and FC level. This may be because blood biomarkers do not directly reflect local inflammation in the colon and are influenced by systemic inflammation and other factors. Conversely, the strong correlation between serum CRP levels and ESR suggests that they both reflect the same systemic inflammatory processes and are valuable for monitoring severe cases as well as those complicated by systemic inflammation. Based on the above findings, fecal biomarkers, such as FC level and fecal occult blood concentration, reflect endoscopic findings better than blood biomarkers, such as CRP level and ESR. However, the disadvantage of fecal biomarker assessments is the delayed results. Therefore, in daily clinical practice, the evaluation of blood biomarkers, such as CRP level and ESR, remains useful in cases of high disease activity. Therefore, we recommend a combined evaluation of these biomarkers. FC level is valuable for screening during outpatient follow-up and monitoring inflammatory activity during remission maintenance, whereas fecal occult blood concentration is particularly suited for detecting proctitis and cases with bleeding. The present study has some limitations. First, this was a single-center, retrospective, observational study with a small sample size. Second, the association between MH and long-term prognosis (e.g., recurrence and surgery rates) was not directly evaluated. Third, levels of other biomarkers, such as LRG and PG-MUM, or results of histological assessments of inflammation were not compared with the endoscopic scores. However, we analyzed longitudinal changes in endoscopic disease activity alongside alterations in the values of the four biomarkers within the same patients and subsequently assessed correlations among them. Conclusion Fecal biomarkers reflected changes in endoscopic scores better than blood biomarkers. Fecal occult blood concentration and FC level sensitively reflect bleeding and inflammation, respectively; therefore, a combined assessment of both of these biomarkers accurately evaluates changes in UC activity. Abbreviations CRP: C-reactive protein CS: colonoscopy ESR: erythrocyte sedimentation rate FC: fecal calprotectin FIT: fecal immunochemical occult blood test LRG: leucine-rich alpha-2 glycoprotein MES: Mayo endoscopic subscore MH: mucosal healing PG-MUM: prostaglandin E-major urinary metabolite S-MES: sum of Mayo endoscopic subscores UC: ulcerative colitis UCEIS: ulcerative colitis endoscopic index of severity ΔB: change in bleeding ΔCRP: change in the serum C-reactive protein level ΔE: change in erosions and ulcers ΔESR: change in the erythrocyte sedimentation rate ΔFC: change in the fecal calprotectin level ΔFIT: change in the fecal immunochemical occult blood test result ΔMES: change in the Mayo endoscopic subscore ΔS-MES: change in the sum of Mayo endoscopic subscores ΔUCEIS: change in the ulcerative colitis endoscopic index of severity ΔV: change in vascular pattern Declarations Ethics approval and consent to participate: The study was approved by the ethics committee of Hamamatsu University School of Medicine (number 24-021). All procedures involving human participants were performed according to the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained via an opt-out method. Consent for publication: Not applicable. Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Funding: Not applicable. Competing interests: The authors declare that they have no competing interests. Acknowledgments: Not applicable Authors’ contributions: YY, NI, and KS designed the study. NI, TT, KT, YA, and MY collected the data. MI, YH, and TY analyzed the data. YY and NI wrote the manuscript. SO and KS provided critical insights regarding the manuscript preparation. All authors read and approved the final manuscript. References Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29. 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Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis. BMC Gastroenterol. 2021;21:197. 10.1186/s12876-021-01788-4 . PMID: 33933033; PMCID: PMC8088576. Table 2 Table 2 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.docx Cite Share Download PDF Status: Posted Version 1 posted 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8241807","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":558231255,"identity":"fa848745-2d05-4251-8411-eccf1b9bfe2c","order_by":0,"name":"Yosuke Yamada","email":"","orcid":"","institution":"Seirei Hamamatsu General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Yamada","suffix":""},{"id":558231258,"identity":"a053c52c-54b2-491f-9840-3687e0d02692","order_by":1,"name":"Natsuki Ishida","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYFACxuYHCQY2cgYwbgOIlMCrhfmYwYeKNGNStLAlSM44cyhxA4oWfEC3/YyBMW/bgfTt7KcTPzDm2Mg2sB9+wGC5A7cWszM5Bo952+7k7uzJ3SzBuC3NuIEnzYBB8gweLQdyQLY8y91wIHeD9N9thxMbGHIYGCTb8Gg5/8ZAmrftcLrB+bebfzBu+5/YwP+GgJYbaSDvH04wuJG7DeiwA4kNEoRsufEYHMiGG2683WbBuC3ZuE3imcEBvH45nwiOSnmD87mbbzBus5Pt509++FgST4hhAjYgPizZQIoWEGD8SLKWUTAKRsEoGMYAAD7rW1nxIv7RAAAAAElFTkSuQmCC","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Natsuki","middleName":"","lastName":"Ishida","suffix":""},{"id":558231259,"identity":"ca7cf0c8-87df-4538-b830-1fd6a396235a","order_by":2,"name":"Tomohiro Takebe","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Takebe","suffix":""},{"id":558231260,"identity":"7c579ee1-cdd0-49e2-b64a-00e283e4d434","order_by":3,"name":"Kenichi Takahashi","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Kenichi","middleName":"","lastName":"Takahashi","suffix":""},{"id":558231261,"identity":"20720331-0a8e-4d6c-8002-0181dc2cd6a9","order_by":4,"name":"Yusuke Asai","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Asai","suffix":""},{"id":558231262,"identity":"ce872f5f-680e-43e9-9ffa-107bcd0cf87f","order_by":5,"name":"Mihoko Yamade","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Mihoko","middleName":"","lastName":"Yamade","suffix":""},{"id":558231263,"identity":"f2004d51-a961-45c9-a97c-6a70ddc227f1","order_by":6,"name":"Moriya Iwaizumi","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Moriya","middleName":"","lastName":"Iwaizumi","suffix":""},{"id":558231264,"identity":"b463e901-f8f2-4bb2-8820-a3c073eb0a6f","order_by":7,"name":"Yasushi Hamaya","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yasushi","middleName":"","lastName":"Hamaya","suffix":""},{"id":558231265,"identity":"203bff24-ec63-402d-8aa8-117746d71516","order_by":8,"name":"Takanori Yamada","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takanori","middleName":"","lastName":"Yamada","suffix":""},{"id":558231266,"identity":"705ada34-9f86-46a1-9d04-9a4e3f47b141","order_by":9,"name":"Satoshi Osawa","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Osawa","suffix":""},{"id":558231267,"identity":"51db7444-e1f0-4765-9de0-8b5a0f2249aa","order_by":10,"name":"Ken Sugimoto","email":"","orcid":"","institution":"Hamamatsu University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Ken","middleName":"","lastName":"Sugimoto","suffix":""}],"badges":[],"createdAt":"2025-11-30 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16:40:39","extension":"html","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":113856,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/3d7bc6d5ac13e6e41859f091.html"},{"id":98425890,"identity":"0e20bb51-93e6-40ad-a89d-7915acfe5107","added_by":"auto","created_at":"2025-12-17 16:35:20","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":260944,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations among variations in the Mayo endoscopic subscore and variations in biomarkers\u003c/p\u003e\n\u003cp\u003e(a) Scatter plot of ΔMES and ΔFIT\u003c/p\u003e\n\u003cp\u003e(b) Scatter plot of ΔMES and ΔFC\u003c/p\u003e\n\u003cp\u003e(c) Scatter plot of ΔMES and ΔCRP\u003c/p\u003e\n\u003cp\u003e(d) Scatter plot of ΔMES and ΔESR\u003c/p\u003e\n\u003cp\u003eΔCRP, change in the serum C-reactive protein level; ΔESR, change in the erythrocyte sedimentation rate; ΔFC, change in the fecal calprotectin level; ΔFIT, change in the fecal immunochemical occult blood test result; ΔMES, change in the Mayo endoscopic subscore\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/d01421525ec4499d8cf0b356.png"},{"id":98047861,"identity":"d82877a4-3d8a-4c70-8a12-39e767b595a8","added_by":"auto","created_at":"2025-12-12 08:30:41","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":273566,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations among variations in the ulcerative colitis endoscopic index of severity and variations in biomarkers\u003c/p\u003e\n\u003cp\u003e(a) Scatter plot of ΔMES and ΔFIT\u003c/p\u003e\n\u003cp\u003e(b) Scatter plot of ΔUCEIS and ΔFC\u003c/p\u003e\n\u003cp\u003e(c) Scatter plot of ΔUCEIS and ΔCRP\u003c/p\u003e\n\u003cp\u003e(d) Scatter plot of ΔUCEIS and ΔESR\u003c/p\u003e\n\u003cp\u003eΔCRP, change in the serum C-reactive protein level; ΔESR, change in the erythrocyte sedimentation rate; ΔFC, change in the fecal calprotectin level; ΔFIT, change in the fecal immunochemical occult blood test result; ΔUCEIS, change in the ulcerative colitis endoscopic index of severity\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/d08332c22e430cb9eca7ca3d.png"},{"id":98047863,"identity":"84caba87-7453-40a7-a91a-e7a9099e5b97","added_by":"auto","created_at":"2025-12-12 08:30:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":294754,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations among variations in the sum of the Mayo endoscopic subscores and variations in biomarkers\u003c/p\u003e\n\u003cp\u003e(a) Scatter plot of ΔS-MES and ΔFIT\u003c/p\u003e\n\u003cp\u003e(b) Scatter plot of ΔS-MES and ΔFC\u003c/p\u003e\n\u003cp\u003e(c) Scatter plot of ΔS-MES and ΔCRP\u003c/p\u003e\n\u003cp\u003e(d) Scatter plot of ΔS-MES and ΔESR\u003c/p\u003e\n\u003cp\u003eΔCRP, change in the serum C-reactive protein level; ΔESR, change in the erythrocyte sedimentation rate; ΔFC, change in the fecal calprotectin level; ΔFIT, change in the fecal immunochemical occult blood test result; ΔS-MES, change in the sum of Mayo endoscopic subscores\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/0e5b372e6bb576a4aecb1783.png"},{"id":98427224,"identity":"0af7da05-6d70-4420-b765-396539f0549b","added_by":"auto","created_at":"2025-12-17 16:40:00","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":180828,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelations among variations in fecal biomarkers and correlations among variations in blood biomarkers\u003c/p\u003e\n\u003cp\u003e(a) Scatter plot of ΔFC and ΔFIT\u003c/p\u003e\n\u003cp\u003e(b) Scatter plot of ΔCRP and ΔESR\u003c/p\u003e\n\u003cp\u003eΔCRP, change in the serum C-reactive protein level; ΔESR, change in the erythrocyte sedimentation rate; ΔFC, change in the fecal calprotectin level; ΔFIT, change in the fecal immunochemical occult blood test result\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/640ae48bc692378304a1e0cc.png"},{"id":99788209,"identity":"c2954f07-7c3c-49aa-b44d-b15e9fc24dfc","added_by":"auto","created_at":"2026-01-08 12:45:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1593877,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/3afd8ee7-3b13-4b88-aea2-a109fde3fee2.pdf"},{"id":98047859,"identity":"15e5b185-53d8-4a0d-8a72-2e9306a3e226","added_by":"auto","created_at":"2025-12-12 08:30:41","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":19671,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-8241807/v1/ee9729297ad284a3f77c78c9.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of changes in biomarkers with changes in endoscopic scores in patients with ulcerative colitis: a single-center, retrospective, observational study","fulltext":[{"header":"Background","content":"\u003cp\u003eUlcerative colitis (UC) is a chronic inflammatory condition that usually follows a remitting-relapsing course, with symptoms such as diarrhea, rectal bleeding, and abdominal pain [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Accurate assessment of disease activity is essential in patients with UC to improve disease management and prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Assessment of disease activity has traditionally relied on clinical symptoms; however, colonoscopy (CS) is the gold standard assessment.\u003c/p\u003e\u003cp\u003eAchieving mucosal healing (MH) is associated with decreased hospitalizations and resections, as well as reduced incidence of colorectal cancer in patients with UC [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, MH induces sustained clinical remission [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. CS is invasive, expensive, time-consuming, and associated with a risk of complications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, performing CS frequently for routine monitoring is difficult. Accordingly, reliable, non-invasive biomarkers that precisely reflect intestinal inflammation and predict MH are essential.\u003c/p\u003e\u003cp\u003eSeveral non-invasive assessments of biomarkers have been used to evaluate disease activity in patients with UC. Although serum C-reactive protein (CRP) level and erythrocyte sedimentation rate (ESR) assessments are simple and provide immediate results, they can only indicate systemic inflammatory responses and do not directly reflect endoscopic damage to the colonic mucosa [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Fecal calprotectin (FC) levels have been reported to significantly correlate with endoscopic disease activity in patients with UC [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. FC levels increase with gut inflammation, characterized by extensive mucosal infiltration by neutrophils [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], and predict clinical recurrence of disease activity in patients with UC [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Occult intestinal bleeding is an important clinical sign of UC, and several studies have demonstrated that fecal occult blood concentration, assessed using the fecal immunochemical occult blood test (FIT), correlate well with the severity of endoscopic inflammation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, comparative studies of biomarkers have reported that fecal occult blood concentration and FC level have stronger correlations with the Mayo Endoscopy subscore (MES) than serum CRP level [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Previous reports have indicated that FC level is significantly correlated with endoscopic scores regardless of the disease type (proctitis, left-sided colitis, and extensive colitis), whereas blood biomarkers, such as serum CRP level and ESR, show weak or no correlations, particularly in patients with proctitis [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, the correlations of these biomarkers vary depending on the stage of disease. For example, according to Ishida et al., during the MH phase (MES: 0, 1), FC level and fecal occult blood concentration had stronger correlations with the total colonic inflammation score than serum CRP level. In contrast, during the endoscopic active phase (MES: 2, 3), serum CRP level correlated significantly stronger with the total colonic inflammation score than FC level and fecal occult blood concentration [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Thus, diverse findings have been reported regarding the ability of each biomarker to reflect different levels of disease activity or specific inflammatory characteristics of UC. Only one study had compared variations in fecal occult blood concentration, FC level, serum CRP level, and ESR with endoscopic activity in patients with UC [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the present study, we aimed to assess the usefulness of FC level, fecal occult blood concentration, serum CRP level, and ESR in predicting disease activity in patients with UC by comparing changes in the values of these biomarkers and endoscopic scores obtained using CS performed for the entire colon.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Patients and study design\u003c/h2\u003e\u003cp\u003eThis study included 97 patients with UC who underwent CS at Hamamatsu University School of Medicine between January 2019 and December 2024. Three CS records (comprising two intervals) per patient were assessed in 48 patients, and two CS records (comprising one interval) per patient were assessed in the remaining 49 patients. In total, 145 intervals were assessed. UC was diagnosed according to currently established criteria based on typical clinical symptoms, endoscopic findings, and histological evaluation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Patients diagnosed with indeterminate colitis or unclassified inflammatory bowel disease were excluded. Determining the sum of Mayo Endoscopy subscores (S-MES) requires observation of the entire colon; therefore, patients with UC who had undergone prior colorectal surgery were excluded. Furthermore, patients with acute infectious enteritis or those regularly taking aspirin and/or other non-steroidal anti-inflammatory drugs were excluded. The patients included in the study underwent CS for routine follow-up or clinical recurrence of UC. Endoscopic scores, including the MES, S-MES, and ulcerative colitis endoscopic index of severity (UCEIS), were assessed.\u003c/p\u003e\u003cp\u003eThis retrospective observational study aimed to longitudinally assess whether variations in FC level, fecal occult blood concentration, serum CRP level, and ESR corresponded to changes in the three distinct endoscopic scores among patients with UC. The primary endpoint was whether the four biomarker values significantly increased or decreased in response to changes in endoscopic scores during two measurements over time. The secondary endpoint was to evaluate which of the four biomarkers correlated strongly with changes in endoscopic scores.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2. Disease assessment\u003c/h2\u003e\u003cp\u003ePatients with UC underwent bowel preparation before CS using a polyethylene glycol-based electrolyte solution taken orally. UC endoscopic measurements included the MES, S-MES, and UCEIS. An MES of 0 indicated normal or inactive disease; 1 indicated mild disease with erythema, decreased vascular pattern, and mild friability; 2 indicated moderate disease with marked erythema, absence of vascular patterns, friability, and erosions; and 3 indicated severe disease with spontaneous bleeding and ulceration in the lesion with the most severe inflammation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The S-MES was calculated as the sum of the MESs of five colonic segments (ascending, transverse, descending, sigmoid, and rectum), as described above [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The UCEIS was calculated as the sum of three descriptors: vascular pattern (score, 0\u0026ndash;2), erosions and ulcers (score, 0\u0026ndash;3), and bleeding (score, 0\u0026ndash;3) [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. An MES of 0 or 1 was considered indicative of MH.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3. Fecal calprotectin and fecal occult blood concentration measurements\u003c/h2\u003e\u003cp\u003eTo avoid the effects of bleeding related to endoscopy, stool samples were collected on or before the day of the CS. Specimens for both FC assessment and FIT were obtained from the same stool sample. Samples were collected in plastic tubes for FC measurement and shipped at \u0026minus;\u0026thinsp;20\u0026deg;C, as recommended by the laboratory (SRL, Inc., Tokyo, Japan). FC level was measured using Phadia 250 immunoanalyzer (HITACHI Ltd., Tokyo, Japan) and Elia A Calprotectin 2 reagent (Phadia GmbH, Freiburg, Germany), according to fluorescence enzyme immunoassay principles. An FIT collection kit (Eiken Chemical, Tokyo, Japan) was used to collect stool specimens. The samples were immediately processed and examined using OC-SENSOR\u0026reg; io (Eiken Chemical).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4. Serum C-reactive protein level and erythrocyte sedimentation rate measurements\u003c/h2\u003e\u003cp\u003eSerum CRP level and ESR were measured to assess UC activity, according to routine clinical practice. Blood samples were collected within a few days of the endoscopic examination. These measurements were performed at the Laboratory Test Department of Hamamatsu University School of Medicine.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5. Statistical analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS v24 (IBM Corp., Armonk, NY, USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) software [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Spearman's rank correlation coefficient analysis was used to evaluate the correlations among changes in the values of four biomarkers and changes in the three endoscopic scores for the preceding and subsequent CS. Statistical significance was set at P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e\u003c/div\u003e\u003cp\u003e\u003cstrong\u003e2.6. Ethical statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was reviewed and approved by the ethics committee of Hamamatsu University School of Medicine (number 24-021) before the commencement of the research. All procedures involving human participants were performed according to the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained via an opt-out method, and the study details were posted on the hospital\u0026rsquo;s website.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e3.1. Patient characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe characteristics of the patients with UC at the time of first CS (N = 145) are shown in Table 1. The median patient age was 48.0 (interquartile range[IQR], 39.0\u0026ndash;61.0) years, and the median disease duration was 8.0 (IQR, 3.0\u0026ndash;15.0) years. The median FC and fecal occult blood levels were 398.0 \u0026mu;g/g and 30 ng/mL, respectively. The median serum CRP level and ESR were 0.07 mg/dL and 7.0 mm/h, respectively.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 1. Patient characteristics\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"580\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics at the precedent CS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eValue (N = 145)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eAge (years), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;48.0 (39.0\u0026ndash;61.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eMale/Female, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;101 (69.7)/44 (30.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eDisease duration (years), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;8.0 (3.0\u0026ndash;15.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 100%;\"\u003e\n \u003cp\u003eDisease extent, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Extensive colitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;91（62.8）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Left-sided colitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;39（26.9）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Proctitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;15（10.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eCAI (Rachmilewitz index), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;1 (0\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eMES, median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;1 (0\u0026ndash;2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eS-MES, median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;1 (0\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eUCEIS, median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;1 (0\u0026ndash;3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eFC level (\u0026micro;g/g), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;398.0 (76.9\u0026ndash;1810.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eFecal occult blood concentration (ng/mL), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;30 (30\u0026ndash;853)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eSerum CRP level (mg/dL), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;0.07 (0.03\u0026ndash;0.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003eESR (mm/h), median (IQR)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;7.0 (3\u0026ndash;14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 100%;\"\u003e\n \u003cp\u003eMedications during the study, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Oral 5‒ASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;100（70.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Suppository 5‒ASA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;13（9.0）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Systemic steroids\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;17（11.7）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Immunomodulators\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;44（30.3）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 62.5862%;\"\u003e\n \u003cp\u003e\u0026nbsp;Biologics\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 37.4138%;\"\u003e\n \u003cp\u003e\u0026nbsp;56（38.6）\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eCS, colonoscopy; IQR, interquartile range; CAI, clinical activity index; MES, Mayo endoscopic subscore; S-MES, sum of Mayo endoscopic subscores; UCEIS, ulcerative colitis endoscopic index of severity; FC, fecal calprotectin; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; 5-ASA, 5-aminosalicylic acid\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2. Correlations among the biomarkers and endoscopic scores\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrelations between each of the four biomarkers and each of the three endoscopic scores were analyzed (Table 2). The values of the four biomarkers significantly increased and decreased in the MES-increase and MES-decrease subgroups, respectively; no significant change was observed in the MES-no change subgroup. The values of the four biomarkers significantly increased and decreased in the UCEIS-increase and UCEIS-decrease subgroups, respectively; no significant change was observed in the UCEIS-no change subgroup. The values of the four biomarkers significantly increased and decreased in the S-MES-increase and S-MES-decrease subgroups, respectively; no significant change was observed in the S-MES-no change subgroup.\u003c/p\u003e\n\u003cp\u003e[Insert Table 2 here]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.3. Correlations among variations in Mayo Endoscopy Scores and four biomarkers\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFigure 1 shows the correlations among a change in the MES (\u0026Delta;MES) and changes in FIT result (\u0026Delta;FIT), FC level (\u0026Delta;FC), serum CRP level (\u0026Delta;CRP), and ESR (\u0026Delta;ESR) from the precedent to the subsequent CS. Significant correlations were observed among \u0026Delta;MES and changes in the four biomarkers (Fig. 1A-D). However, the correlation between \u0026Delta;MES and \u0026Delta;FC (r = 0.62) was stronger than that among \u0026Delta;MES and changes in other biomarkers (\u0026Delta;FIT, r = 0.57; \u0026Delta;CRP, r = 0.33; \u0026Delta;ESR, r = 0.40). Figure 2 shows the correlations among a change in the UCEIS (\u0026Delta;UCEIS) and \u0026Delta;FIT, \u0026Delta;FC, \u0026Delta;CRP, and \u0026Delta;ESR from the precedent to the subsequent CS. Significant correlations were observed among \u0026Delta;UCEIS and changes in the four biomarkers (Fig. 2A-D). However, the correlation between \u0026Delta;UCEIS and \u0026Delta;FIT was stronger (r = 0.67) than that among \u0026Delta;UCEIS and changes in the other biomarkers (\u0026Delta;FC, r = 0.65; \u0026Delta;CRP, r = 0.42; \u0026Delta;ESR, r = 0.46). We further examined the correlations of \u0026Delta;FIT and \u0026Delta;FC with\u0026nbsp;changes in the UCEIS; changes in vascular pattern (\u0026Delta;V), bleeding (\u0026Delta;B), and erosions and ulcers (\u0026Delta;E) were significantly correlated with both \u0026Delta;FIT and \u0026Delta;FC (Table 3). The correlation coefficient with \u0026Delta;V was greater for \u0026Delta;FC than for \u0026Delta;FIT. In contrast, the correlation coefficients with \u0026Delta;B and \u0026Delta;E were greater for \u0026Delta;FIT than for \u0026Delta;FC. Figure 3 shows the correlations among a change in the S-MES (\u0026Delta;S-MES) and \u0026Delta;FIT, \u0026Delta;FC, \u0026Delta;CRP, and \u0026Delta;ESR from the precedent to the subsequent CS. Significant correlations were observed among \u0026Delta;S-MES and changes in the four biomarkers (Fig. 3A-D). However, the correlation between \u0026Delta;S-MES and \u0026Delta;FC (r = 0.66) was stronger than that among \u0026Delta;S-MES and changes in other biomarkers (\u0026Delta;FIT, r = 0.54; \u0026Delta;CRP, r = 0.39; \u0026Delta;ESR, r = 0.35). A significant correlation was observed between \u0026Delta;FIT and \u0026Delta;FC (r = 0.55; P \u0026lt; 0.001; Fig. 4A) and between \u0026Delta;CRP and \u0026Delta;ESR (r = 0.58; P \u0026lt; 0.001; Fig. 4B).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Table 3. Correlations among changes in fecal biomarker values and ulcerative colitis endoscopic index of severity parameters\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" valign=\"top\" style=\"width: 292px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 292px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;FIT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 292px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;FC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003er\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003er\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"3\" valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;UCEIS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;V\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;B\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026Delta;E\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026Delta;FIT, change in the fecal immunochemical occult blood test result; \u0026Delta;FC, change in the fecal calprotectin level; r, correlation coefficient; \u0026Delta;UCEIS, change in the ulcerative colitis endoscopic index of severity; \u0026Delta;V, change in vascular pattern; \u0026Delta;B, change in bleeding; \u0026Delta;E, change in erosions and ulcers\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eMost studies on endoscopic activity and biomarkers of UC to date have been cross-sectional, with very few longitudinal observational studies examining correlations among endoscopic scores and biomarkers [6, 21, 22]. Hiraoka et al. investigated changes in the MES between the MH and active phases in the same patients using FC level assessment and FIT. They reported that fecal occult blood concentration more accurately mirrored changes during the MH phase than FC level, whereas FC level more reliably reflected alterations during the active phase than fecal occult blood concentration [6]. However, they did not assess the correlations among the UCEIS, S-MES, FC level, and fecal occult blood concentration. Ishida et al. compared changes in the MES and S-MES with changes in prostaglandin E-major urinary metabolite (PG-MUM) and serum CRP levels in the same patients, and reported that PG-MUM reflected endoscopic scores better than serum CRP levels [21]. However, they did not assess the UCEIS and fecal occult blood concentration in relation to bleeding. Aoyama et al. further explored correlations among changes in leucine-rich alpha-2 glycoprotein (LRG), FC level, fecal occult blood concentration, and serum CRP level and alterations in the MES and UCEIS, along with assessments of histological inflammation. They observed that the correlation coefficient between \u0026Delta;FC and \u0026Delta;MES was greater than that between \u0026Delta;FIT and \u0026Delta;MES [22], a finding consistent with the present results. They did not assess changes in the total colonoscopy score. The present study is unique for its longitudinal evaluation of correlations among changes in endoscopic disease activity in UC and temporal variations in the values of the four biomarkers (fecal occult blood concentration, FC level, serum CRP level, and ESR) within the same patient cohort. Moreover, the concurrent comparisons of multiple endoscopic scores proved invaluable for identifying the distinct characteristics of each biomarker. The MES assessment is simple and easy to use in daily clinical practice and is widely used in clinical trials; however, the results show relatively high interobserver variability [23]. The UCEIS is more detailed, objective, and sensitive in reflecting changes in cases of moderate-to-severe inflammation\u0026nbsp;than the MES. It also includes bleeding scores [24]. Another innovative aspect of the present study was the assessment of changes in the S-MES for the entire colon, in conjunction with alterations in fecal biomarkers. Calculation of the S-MES is time-consuming; however, it allows simultaneous assessment of the extent and severity of inflammation, enabling an accurate evaluation of the overall disease state, and is useful for determining treatment efficacy [18].\u003c/p\u003e\n\u003cp\u003eIn the present study, we first examined changes in each biomarker value based on increases, decreases, or no change in the endoscopic scores. Each biomarker value was significantly elevated or reduced, corresponding to increases or decreases in the endoscopic scores. In the absence of changes in the endoscopic scores, the biomarker values did not show any significant variation. Although each biomarker demonstrated utility, we analyzed correlations among changes in biomarker values and changes in endoscopic scores to verify subtle changes. Changes in both fecal occult blood concentration and FC level significantly correlated with changes in endoscopic scores; however, each biomarker reflected distinct endoscopic characteristics. \u0026Delta;FC showed the strongest correlation with both \u0026Delta;MES and \u0026Delta;S-MES, thereby precisely reflecting the extent and severity of inflammation. FC is a neutrophil-derived protein that accurately reflects the extent and intensity of inflammation. Consequently, FC level is strongly correlated with high disease activity. Sonoyama et al. demonstrated that FC level was significantly correlated with endoscopic activity across all disease subgroups, with particularly strong associations observed in cases of left-sided colitis (r = 0.75) and extensive colitis (r = 0.78) [14]. This report supports the results of the present correlation analysis between FC level and the S-MES. On the other hand, fecal occult blood concentration demonstrated the strongest correlation with the UCEIS and a stronger correlation with \u0026Delta;E and \u0026Delta;B than FC level, indicating that it primarily reflects bleeding and superficial mucosal injury rather than the underlying inflammatory process. The correlation coefficient between \u0026Delta;FIT and \u0026Delta;B was greater than that between \u0026Delta;FC and \u0026Delta;B. Sakuraba et al. reported that fecal occult blood concentration reflects endoscopic activity better than FC level in cases of UC with proctitis [25]. The reason for this may be the short retention time of stool, owing to the short distance between the site of inflammation and the anus, and the absence of diarrhea in patients with proctitis. Blood and mucus adhering to the stool surface may cause variability in FC level measurements.\u0026nbsp;Therefore, fecal occult blood concentration is regarded as superior to FC level for evaluating proctitis and active disease states characterized by bleeding, whereas FC level is more effective than fecal occult blood concentration\u0026nbsp;for assessing the overall intensity of inflammation. The combined use of these biomarkers may facilitate a comprehensive and multidimensional evaluation of UC disease activity.\u003c/p\u003e\n\u003cp\u003eSerum CRP level and ESR also correlated with the endoscopic scores; however, their correlation coefficients were lower than those of fecal occult blood concentration and FC level. This may be because blood biomarkers do not directly reflect local inflammation in the colon and are influenced by systemic inflammation and other factors. Conversely, the strong correlation between serum CRP levels and ESR suggests that they both reflect the same systemic inflammatory processes and are valuable for monitoring severe cases as well as those complicated by systemic inflammation.\u003c/p\u003e\n\u003cp\u003eBased on the above findings, fecal biomarkers, such as FC level and fecal occult blood concentration, reflect endoscopic findings better than blood biomarkers, such as CRP level and ESR. However, the disadvantage of fecal biomarker assessments is the delayed results. Therefore, in daily clinical practice, the evaluation of blood biomarkers, such as CRP level and ESR, remains useful in cases of high disease activity. Therefore, we recommend a combined evaluation of these biomarkers. FC level is valuable for screening during outpatient follow-up and monitoring inflammatory activity during remission maintenance, whereas fecal occult blood concentration is particularly suited for detecting proctitis and cases with bleeding.\u003c/p\u003e\n\u003cp\u003eThe present study has some limitations. First, this was a single-center, retrospective, observational study with a small sample size. Second, the association between MH and long-term prognosis (e.g., recurrence and surgery rates) was not directly evaluated. Third, levels of other biomarkers, such as LRG and PG-MUM, or results of histological assessments of inflammation were not compared with the endoscopic scores. However, we analyzed longitudinal changes in endoscopic disease activity alongside alterations in the values of the four biomarkers within the same patients and subsequently assessed correlations among them.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eFecal biomarkers reflected changes in endoscopic scores better than blood biomarkers. Fecal occult blood concentration and FC level sensitively reflect bleeding and inflammation, respectively; therefore, a combined assessment of both of these biomarkers accurately evaluates changes in UC activity.\u003c/p\u003e\n"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eCRP: C-reactive protein\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCS: colonoscopy\u003c/li\u003e\n \u003cli\u003eESR: erythrocyte sedimentation rate\u003c/li\u003e\n \u003cli\u003eFC:\u0026nbsp;fecal calprotectin\u003c/li\u003e\n \u003cli\u003eFIT:\u0026nbsp;fecal immunochemical occult blood test\u003c/li\u003e\n \u003cli\u003eLRG:\u0026nbsp;leucine-rich alpha-2 glycoprotein\u003c/li\u003e\n \u003cli\u003eMES: Mayo endoscopic subscore\u003c/li\u003e\n \u003cli\u003eMH: mucosal healing\u003c/li\u003e\n \u003cli\u003ePG-MUM: prostaglandin E-major urinary metabolite\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eS-MES: sum of Mayo endoscopic subscores\u003c/li\u003e\n \u003cli\u003eUC: ulcerative colitis\u003c/li\u003e\n \u003cli\u003eUCEIS: ulcerative colitis endoscopic index of severity\u003c/li\u003e\n \u003cli\u003e\u0026Delta;B: change in bleeding\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026Delta;CRP:\u0026nbsp;change in the serum C-reactive protein level\u003c/li\u003e\n \u003cli\u003e\u0026Delta;E: change in erosions and ulcers\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u0026Delta;ESR:\u0026nbsp;change in the\u0026nbsp;erythrocyte sedimentation rate\u003c/li\u003e\n \u003cli\u003e\u0026Delta;FC: change in the\u0026nbsp;fecal calprotectin level\u003c/li\u003e\n \u003cli\u003e\u0026Delta;FIT: change in the\u0026nbsp;fecal immunochemical occult blood test result\u003c/li\u003e\n \u003cli\u003e\u0026Delta;MES:\u0026nbsp;change in the\u0026nbsp;Mayo endoscopic subscore\u003c/li\u003e\n \u003cli\u003e\u0026Delta;S-MES:\u0026nbsp;change in the\u0026nbsp;sum of Mayo endoscopic subscores\u003c/li\u003e\n \u003cli\u003e\u0026Delta;UCEIS:\u0026nbsp;change in the ulcerative colitis endoscopic index of severity\u003c/li\u003e\n \u003cli\u003e\u0026Delta;V: change in vascular pattern\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e The study was approved by the ethics committee of Hamamatsu University School of Medicine (number 24-021). All procedures involving human participants were performed according to the ethical standards of the institutional research committee and the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained via an opt-out method.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u0026nbsp;\u003c/strong\u003eYY, NI, and KS designed the study. NI, TT, KT, YA, and MY collected the data. MI, YH, and TY analyzed the data. YY and NI wrote the manuscript. SO and KS provided critical insights regarding the manuscript preparation. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePodolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417\u0026ndash;29.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGarcia-Planella E, Ma\u0026ntilde;osa M, Van Domselaar M, Gordillo J, Zabana Y, Cabr\u0026eacute; E, et al. Long-term outcome of ulcerative colitis in patients who achieve clinical remission with a first course of corticosteroids. Dig Liver Dis. 2012;44:206\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePeyrin-Biroulet L, Sandborn W, Sands BE, Reinisch W, Bemelman W, Bryant RV, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. 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PMID: 23208313.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIshida N, Tamura S, Miyazu T, Tani S, Yamade M, Iwaizumi M, et al. Comparison between prostaglandin E-major urinary metabolite and C-reactive protein levels to reflect endoscopic scores in patients with ulcerative colitis. Sci Rep. 2021;11:16205. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-021-95761-6\u003c/span\u003e\u003cspan address=\"10.1038/s41598-021-95761-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 34376764; PMCID: PMC8355113.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAoyama Y, Hiraoka S, Yasutomi E, Inokuchi T, Tanaka T, Takei K, et al. Changes of leucine-rich alpha 2 glycoprotein could be a marker of changes of endoscopic and histologic activity of ulcerative colitis. Sci Rep. 2025;15:5248. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41598-025-89615-8\u003c/span\u003e\u003cspan address=\"10.1038/s41598-025-89615-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 39939376; PMCID: PMC11822068.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eViscido A, Valvano M, Stefanelli G, Capannolo A, Castellini C, Onori E, et al. Systematic review and meta-analysis: the advantage of endoscopic Mayo score 0 over 1 in patients with ulcerative colitis. BMC Gastroenterol. 2022;22:92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12876-022-02157-5\u003c/span\u003e\u003cspan address=\"10.1186/s12876-022-02157-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 35240984; PMCID: PMC8895505.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTravis SPL, Schnell D, Krzeski P, Abreu MT, Altman DG, Colombel JF, et al. Developing an instrument to assess the endoscopic severity of ulcerative colitis: the Ulcerative Colitis Endoscopic Index of Severity (UCEIS). Gut. 2012;61:535\u0026ndash;42. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/gutjnl-2011-300486\u003c/span\u003e\u003cspan address=\"10.1136/gutjnl-2011-300486\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2011 Oct 13. PMID: 21997563; PMCID: PMC3292713.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSakuraba A, Nemoto N, Hibi N, Ozaki R, Tokunaga S, Kikuchi O, et al. Extent of disease affects the usefulness of fecal biomarkers in ulcerative colitis. BMC Gastroenterol. 2021;21:197. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12876-021-01788-4\u003c/span\u003e\u003cspan address=\"10.1186/s12876-021-01788-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. PMID: 33933033; PMCID: PMC8088576.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Table 2","content":"\u003cp\u003eTable 2 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"ulcerative colitis, biomarker, fecal immunochemical occult blood test, fecal calprotectin","lastPublishedDoi":"10.21203/rs.3.rs-8241807/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8241807/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eFecal occult blood concentration, fecal calprotectin (FC) level, serum C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) are valuable biomarkers for ulcerative colitis (UC); however, their clinical utility for longitudinal disease assessment requires further clarification. This retrospective, observational study aimed to assess the correlations among changes in the values of these biomarkers and endoscopic activity scores in patients with UC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe examined the relationship between longitudinal variations in endoscopic activity scores, including the Mayo endoscopic subscore (MES), ulcerative colitis endoscopic index of severity (UCEIS), and sum of Mayo endoscopic subscores (S-MES), and corresponding changes in biomarker values within the same cohort of patients with UC using Spearman's rank correlation coefficient analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAll endoscopic scores and biomarkers were significantly correlated with disease activity, with corresponding increases or decreases (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Changes in the MES had the strongest correlation with changes in FC level (r\u0026thinsp;=\u0026thinsp;0.62). The changes in the UCEIS had the strongest correlation with changes in fecal occult blood concentration (r\u0026thinsp;=\u0026thinsp;0.67). Changes in S-MES had the strongest correlation with changes in FC level (r\u0026thinsp;=\u0026thinsp;0.66). Changes in fecal occult blood concentration and FC level were strongly correlated (r\u0026thinsp;=\u0026thinsp;0.55), as were changes in serum CRP level and ESR (r\u0026thinsp;=\u0026thinsp;0.58).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eAll four biomarkers reflected endoscopic activity in UC; however, changes in fecal occult blood concentration and FC level had stronger correlations with changes in endoscopic scores than changes in blood biomarker values. FC level assessment is valuable for monitoring inflammatory activity during remission maintenance, whereas fecal occult blood concentration accurately reflects mucosal bleeding. Serum CRP level and ESR are useful adjunctive biomarkers, particularly in cases of increased disease activity.\u003c/p\u003e","manuscriptTitle":"Comparison of changes in biomarkers with changes in endoscopic scores in patients with ulcerative colitis: a single-center, retrospective, observational study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-12 08:30:37","doi":"10.21203/rs.3.rs-8241807/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1f15718b-0146-49db-82f3-aa71c9a6aa0a","owner":[],"postedDate":"December 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-12-26T06:24:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-12 08:30:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8241807","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8241807","identity":"rs-8241807","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}