Comparison of Changes in Biomarkers With Changes in Endoscopic Scores in Patients With Ulcerative Colitis: A Single‐Center, Retrospective, Observational Study

ABSTRACT

Aim

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 remains unclear. This retrospective, observational study assessed correlations between biomarker changes and endoscopic activity scores in UC.

Methods

Spearman's rank correlation coefficient analysis was applied to examine 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 biomarker changes in patients with UC.

Results

The study included 97 patients, contributing to 145 observation intervals (48 contributed two intervals each and 49 contributed one each). All endoscopic scores and biomarkers were significantly correlated with disease activity, with corresponding increases or decreases (p < 0.05). Changes in MES and S‐MES correlated most strongly with FC level changes (r = 0.62 and 0.66, respectively). Changes in the UCEIS exhibited the strongest correlation with fecal occult blood concentration changes (r = 0.67). Changes in fecal occult blood and FC (r = 0.55) and in serum CRP and ESR (r = 0.58) were strongly correlated.

Conclusions

All four biomarkers reflected endoscopic activity in UC. Changes in fecal occult blood concentration and FC level had stronger correlations with endoscopic score changes than blood biomarker concentration changes. FC assessment is valuable for monitoring inflammatory activity during remission maintenance, whereas fecal occult blood concentration reflects mucosal bleeding. Serum CRP level and ESR are useful adjunctive biomarkers, particularly in cases of increased disease activity.

1. Introduction

Ulcerative colitis (UC) is a chronic inflammatory condition usually characterized by a remitting–relapsing course, with symptoms including 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 and a 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 complication risk [5, 6]. Therefore, performing CS frequently for routine monitoring is difficult. Hence, reliable, noninvasive biomarkers that precisely reflect intestinal inflammation and predict MH are essential.

Several noninvasive assessments of biomarkers have been implemented 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 also significantly correlate with endoscopic disease activity in patients with UC [8]. FC levels increase with gut inflammation due to extensive mucosal infiltration of 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 fecal occult blood concentration, assessed using the fecal immunochemical occult blood test (FIT), correlates well with the severity of endoscopic inflammation [11, 12]. Furthermore, comparative studies of biomarkers have reported stronger correlations of fecal occult blood concentration and FC level with the Mayo Endoscopy subscore (MES) than serum CRP level [11]. 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 disease stage. For example, Ishida et al. [14] revealed that during the MH phase (MES: 0, 1), FC level and fecal occult blood concentration exhibited 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]. The present study 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.

2. 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. Notably, 97 patients contributed to 145 observation intervals. 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. 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. As determining the sum of Mayo Endoscopy subscores (S‐MES) requires full colon assessment, 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 nonsteroidal 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 longitudinally assessed whether variations in FC level, fecal occult blood concentration, serum CRP level, and ESR correspond 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. Detailed information regarding treatment changes between endoscopies could not be systematically obtained because of the retrospective study design.

2.2. Disease Assessment

Patients with UC underwent bowel preparation with an orally administered polyethylene glycol‐based electrolyte solution before CS. 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. Endoscopic images were evaluated by multiple experienced gastroenterologists using validated scoring systems (MES, UCEIS, and S‐MES). As this was a retrospective study based on routine clinical practice, formal blinding to biomarker results was not systematically performed, and inter‐observer agreement statistics were not assessed.

2.3. FC and Fecal Occult Blood Concentration Measurements

To avoid the effects of bleeding related to endoscopy, stool samples were collected on or before the CS day. Specimens for both FC assessment and FIT were obtained from the same stool sample. Samples were collected in plastic tubes for FC measurement and transported at −20°C according to the laboratory protocol (SRL Inc., Tokyo, Japan). FC levels were measured using a Phadia 250 immunoanalyzer (Hitachi Ltd., Tokyo, Japan) with the EliA Calprotectin 2 reagent (Phadia GmbH, Freiburg, Germany) according to fluorescence enzyme immunoassay principles. The EliA Calprotectin 2 assay has an analytical measuring range of 4.0 to ≥ 6000 μg/g stool, with reported interassay coefficients of variation of approximately 3.7% to 7.5% according to the manufacturer's specifications. Stool specimens were collected using an FIT collection kit (Eiken Chemical, Tokyo, Japan). Samples were immediately processed and analyzed using the OC‐SENSOR io (Eiken Chemical). The analytical limit of detection for hemoglobin on this platform is approximately 1.2 ng/mL according to the manufacturer's specifications.

2.4. Serum CRP Level and ESR Rate Measurements

Serum CRP level and ESR were measured to assess UC activity, according to routine clinical practice. These measurements were performed at the Laboratory Test Department of Hamamatsu University School of Medicine. Blood samples were obtained within a few days of endoscopy as part of routine clinical care. Exact sampling intervals relative to endoscopy were not consistently available in the retrospective dataset.

2.5. Statistical Analysis

Statistical analyses were performed using SPSS v24 (IBM Corp., Armonk, New York, USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan) software [20]. Wilcoxon signed‐rank test was used for comparisons between paired measurements. 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. Changes (Δ) were calculated as the value at the second endoscopy minus the value at the first endoscopy. Units were as follows: FC (μg/g), FIT (ng/mL), CRP (mg/dL), and ESR (mm/h). As a sensitivity analysis, correlation analyses were repeated using only one observation interval per patient (first interval) to account for potential within‐patient clustering. 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 (approval 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.

3. 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 (39–61)
Male/female, n (%)	101 (69.7)/44 (30.3)
Disease duration (years), median (IQR)	8.0 (3–15)
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)
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)
Suppository 5‐ASA	13 (9)
Systemic steroids	17 (11.7)
Immunomodulators	44 (30.3)
Biologics	56 (38.6)

Abbreviations: 5‐ASA, 5‐aminosalicylic acid; CAI, clinical activity index; CS, colonoscopy; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; FC, fecal calprotectin; IQR, interquartile range; MES, Mayo endoscopic subscore; S‐MES, sum of Mayo endoscopic subscores; UCEIS, ulcerative colitis endoscopic index of severity.

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.

TABLE 2.

Correlations among biomarkers and endoscopic scores.

Variable		Increase			No change			Decrease
		1st CS	2nd CS	p	1st CS	2nd CS	p	1st CS	2nd CS	p
MES	Fecal occult blood concentration (ng/mL), median (IQR)	30 (30–66.8)	179 (30–485.0)	0.005	30 (30–127.5)	30 (30–83)	0.872	718 (60–4195)	30 (30–59)	< 0.001
	FC level (μg/g), median (IQR)	139 (50.3–525.8)	750.5 (253.6–2542.5)	< 0.001	167 (45.5–744)	211.5 (51.6–868)	0.171	2170 (391.5–5230)	126 (28.7–379)	< 0.001
	Serum CRP level (mg/dL), median (IQR)	0.05 (0.03–0.14)	0.12 (0.04–0.42)	0.007	0.06 (0.02–0.13)	0.06 (0.03–0.16)	0.828	0.08 (0.04–0.25)	0.04 (0.02–0.14)	0.002
	ESR (mm/h), median (IQR)	7.5 (3.3–17.3)	10 (6.3–26)	0.002	7 (3–11.3)	8 (3–12)	0.695	8 (4–14)	6 (2–9.5)	0.001
UCEIS	Fecal occult blood concentration (ng/mL), median (IQR)	30 (30–148)	239 (30–486)	0.003	30 (30–30)	30 (30–30)	0.824	571 (54.8–3280)	30 (30–116)	< 0.001
	FC level (μg/g), median (IQR)	387 (53.7–795)	771 (350–2690)	< 0.001	96.9 (37.1–276.8)	176 (49.1–379.5)	0.970	1795 (394.8–5175)	168 (39.2–568.5)	< 0.001
	Serum CRP level (mg/dL), median (IQR)	0.06 (0.03–0.13)	0.12 (0.05–0.37)	0.001	0.04 (0.02–0.10)	0.04 (0.02–0.13)	0.684	0.09 (0.04–0.27)	0.05 (0.02–0.14)	< 0.001
	ESR (mm/h), median (IQR)	7 (3–18)	10 (5–28)	0.006	6 (2–9)	8 (3–11.3)	0.060	9 (5–15.3)	6.5 (2.8–10)	< 0.001
S‐MES	Fecal occult blood concentration (ng/mL), median (IQR)	30 (30–240.3)	241.5 (30–1417.5)	0.024	30 (30–30)	30 (30–30)	0.380	376 (55–2840)	30 (30–115)	< 0.001
	FC level (μg/g), median (IQR)	355 (56.5–777)	956 (370.3–2865)	< 0.001	113 (37.3–321.8)	176 (48.5–377)	0.551	2170 (411–5240)	154 (37.2–414)	< 0.001
	Serum CRP level (mg/dL), median (IQR)	0.06 (0.03–0.1)	0.12 (0.05–0.47)	0.004	0.05 (0.02–0.11)	0.05 (0.03–0.12)	0.851	0.08 (0.04–0.27)	0.04 (0.02–0.14)	0.001
	ESR (mm/h), median (IQR)	8 (3.8–18)	9 (5.8–28.8)	0.037	6 (2.75–9.25)	8 (3–11.3)	0.193	8 (3–14)	6 (2–9)	0.002

Abbreviations: CRP, C‐reactive protein; CS, colonoscopy; ESR, erythrocyte sedimentation rate; FC, fecal calprotectin; IQR, interquartile range; MES, Mayo endoscopic subscore; S‐MES, sum of Mayo endoscopic subscores; UCEIS, ulcerative colitis endoscopic index of severity.

3.3. Correlations Among Variations in MES 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 (Figure 1a–d). However, the correlation between ΔMES and ΔFC (r = 0.62, 95% confidence interval [CI], 0.50–0.72, p < 0.001) was stronger than that among ΔMES and changes in other biomarkers (ΔFIT, r = 0.57, 95% CI, 0.45–0.67, p < 0.001; ΔCRP, r = 0.33, 95% CI, 0.16–0.47, p < 0.001; ΔESR, r = 0.40, 95% CI, 0.25–0.54, p < 0.001). 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 (Figure 2a–d). However, the correlation between ΔUCEIS and ΔFIT was stronger (r = 0.67, 95% CI, 0.55–0.76, p < 0.001) than that among ΔUCEIS and changes in the other biomarkers (ΔFC, r = 0.65, 95% CI, 0.50–0.77, p < 0.001; ΔCRP, r = 0.42, 95% CI, 0.26–0.55, p < 0.001; ΔESR, r = 0.46, 95% CI, 0.31–0.59, p < 0.001). In the sensitivity analysis restricted to one interval per patient (n = 97), Spearman correlation coefficients were similar in magnitude to those in the full dataset, and statistical significance was preserved (Table S1). We further examined the correlations of ΔFIT and ΔFC with changes in the UCEIS. Notably, 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 (Figure 3a–d). However, the correlation between ΔS‐MES and ΔFC (r = 0.66, 95% CI, 0.53–0.76, p < 0.001) was stronger than that among ΔS‐MES and changes in other biomarkers (ΔFIT, r = 0.54, 95% CI, 0.38–0.67, p < 0.001; ΔCRP, r = 0.39, 95% CI, 0.22–0.54, p < 0.001; ΔESR, r = 0.38, 95% CI, 0.22–0.53, p < 0.001). A significant correlation was observed between ΔFIT and ΔFC (r = 0.55, 95% CI, 0.40–0.70, p < 0.001; Figure 4a) and between ΔCRP and ΔESR (r = 0.58, 95% CI, 0.43–0.70, p < 0.001; Figure 4b).

FIGURE 1.

Correlations among variations in the Mayo endoscopic subscore and variations in biomarkers. (a) Scatter plot of ΔMES and ΔFIT. (b) Scatter plot of ΔMES and ΔFC. (c) Scatter plot of ΔMES and ΔCRP. (d) Scatter plot of ΔMES and ΔESR. ΔCRP, 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.

FIGURE 2.

Correlations among variations in the ulcerative colitis endoscopic index of severity and variations in biomarkers. (a) Scatter plot of ΔUCEIS and ΔFIT. (b) Scatter plot of ΔUCEIS and ΔFC. (c) Scatter plot of ΔUCEIS and ΔCRP. (d) Scatter plot of ΔUCEIS and ΔESR. ΔCRP, 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.

TABLE 3.

Correlations among changes in fecal biomarker values and ulcerative colitis endoscopic index of severity parameters.

Variable		ΔFIT		ΔFC
		r	p	r	p
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

Abbreviations: ΔB, change in bleeding; ΔE, change in erosions and ulcers; ΔFIT, change in the fecal immunochemical occult blood test result; ΔFC, change in the fecal calprotectin level; ΔUCEIS, change in the ulcerative colitis endoscopic index of severity; ΔV, change in vascular pattern; r, correlation coefficient.

FIGURE 3.

Correlations among variations in the sum of the Mayo endoscopic subscores and variations in biomarkers. (a) Scatter plot of ΔS‐MES and ΔFIT. (b) Scatter plot of ΔS‐MES and ΔFC. (c) Scatter plot of ΔS‐MES and ΔCRP. (d) Scatter plot of ΔS‐MES and ΔESR. ΔCRP, 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.

FIGURE 4.

Correlations among variations in fecal biomarkers and correlations among variations in blood biomarkers. (a) Scatter plot of ΔFC and ΔFIT. (b) Scatter plot of ΔCRP and ΔESR. ΔCRP, 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.

4. Discussion

Most studies on endoscopic activity and UC biomarkers are cross‐sectional, with very few longitudinal observational studies examining correlations among endoscopic scores and biomarkers [6, 21, 22]. Hiraoka et al. [6] investigated changes in the MES between the MH and active phases in the same patients using FC level assessment and FIT. The 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, the correlations among the UCEIS, S‐MES, FC level, and fecal occult blood concentration were not assessed in this previous study. Ishida et al. [21] 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. However, they did not assess the UCEIS and fecal occult blood concentration with respect to bleeding. Aoyama et al. [22] 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. Notably, the correlation coefficient between ΔFC and ΔMES was greater than that between ΔFIT and ΔMES [22], a finding consistent with the present results. However, changes in the total colonoscopy score were not assessed previously. 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 apply 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. Moreover, 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. Although calculation of the S‐MES is time‐consuming, it allows simultaneous assessment of inflammation extent and severity, 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 inflammation extent and severity. FC is a neutrophil‐derived protein that accurately reflects inflammation extent and intensity. Consequently, FC level is strongly correlated with high disease activity. Sonoyama et al. [13] demonstrated a significant correlation of FC level 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) [13]. This supports the results of the present correlation analysis between FC level and the S‐MES. Meanwhile, fecal occult blood concentration exhibited 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. [25] reported that fecal occult blood concentration reflects endoscopic activity better than FC level in cases of UC with proctitis. This may be attributed to the short retention time of stool, owing to the short distance between the inflammation site 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. Accordingly, 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 suitable for detecting proctitis and cases with bleeding. Although moderate correlations were observed between changes in fecal biomarker levels and endoscopic activity, correlation coefficients reflect association rather than diagnostic accuracy at the individual patient level. Therefore, these findings should not be interpreted as establishing specific clinical cut‐off values for detecting meaningful endoscopic change. Further prospective studies are necessary to evaluate discriminatory performance and determine clinically applicable thresholds.

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. Future studies incorporating emerging biomarkers, such as LRG, and standardized histological assessment may better clarify the relationship between noninvasive markers and deep or histological remission. Fourth, although blood sampling was performed within a short time window around endoscopy in routine practice, precise timing was not systematically recorded. Therefore, minor temporal misalignment between blood biomarkers and endoscopic assessment cannot be completely excluded. Fifth, although multiple correlations were assessed, the biomarkers were selected a priori based on their established clinical relevance in UC. Given the exploratory study design and consistent findings across endoscopic scores, formal adjustment for multiple comparisons was not performed. 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.

5. Conclusions

Changes in FIT and FC were moderately associated with changes in endoscopic activity. Biologically, FIT concentrations likely reflect mucosal bleeding, whereas FC levels reflect intestinal inflammation. These findings suggest potential utility for noninvasive monitoring of disease activity; however, further studies are crucial to determine their clinical applicability for guiding individual treatment decisions.

Funding

The authors have nothing to report.

Ethics Statement

The study was approved by the ethics committee of Hamamatsu University School of Medicine (approval 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.

Consent

Informed consent was obtained via an opt‐out method.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Sensitivity analysis of Spearman correlations restricted to one observation interval per patient (first interval only, n = 97).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.