Introduction

Ulcerative colitis (UC) is a chronic inflammatory disease of the colorectum with an increased incidence and prevalence in Korea [1]. UC is a progressive disease, similar to Crohn disease; however, its treatment has evolved to focus on achieving more objective goals, as disease course improvement cannot be achieved solely through clinical remission [2-4]. Hence, experts in inflammatory bowel disease (IBD) have proposed appropriate treatment targets and published revised guidelines in 2021 [4,5]. According to Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) I and II, the goal of treatment needs to be achieved with a flexible clinical course. Furthermore, the target should be defined clearly because IBD is a complex disease. International guidelines need to be established to help achieve these objectives in clinical practice [4]. Considering these aspects, among the several treatment targets adopted, endoscopic resolution has been important in patients with UC because of its strong predictive value for clinical remission maintenance, hospitalization rate reduction, and reduced risk of colectomy [6,7].

According to the treat-to-target strategy in IBD, achieving endoscopic remission is considered as a primary therapeutic goal, with histological remission regarded as a desirable adjunctive target [8]. Although endoscopic healing has traditionally guided treatment decisions, several studies have highlighted the discordance between endoscopic and histological activities [9-11]. Notably, a substantial proportion of patients who achieve endoscopic remission exhibit persistent histological inflammation, which has been associated with worse clinical outcomes such as increased corticosteroid usage and hospitalization rates. Therefore, evaluating the relationship between histological and endoscopic activities at the time of diagnosis may offer meaningful insights into disease behavior and treatment responses in UC [9,10].

Methods

Ethics statement: This study was approved by the Institutional Review Board (IRB) of Yeungnam University Hospital (IRB No: 2022-09-017), and the requirement for informed consent was waived.

1. Patients and treatment

Our hospital (Yeungnam University Hospital) recorded 205 patients newly diagnosed with UC between March 2015 and February 2022. This study excluded patients who had follow-ups within 1 year or had no endoscopic or histological findings during diagnosis and within the first year. The medical records of the 51 patients who were followed up at our hospital for at least 1 year were retrospectively reviewed (Fig. 1). Histological and endoscopic findings and laboratory data during diagnosis and follow-up were reviewed, and the correlation between histological activity at diagnosis and clinical endoscopic response at follow-up was analyzed.

2. Definitions

Standardized scoring systems were used to evaluate the relationship between histological and endoscopic activities in patients with UC. Histological activity was assessed using the Nancy histological index [12], which grades inflammation from 0 (no significant histological disease) to 4 (severe disease). All histological assessments were performed by a single gastrointestinal pathologist (MJ Gu), with a focus on crypt architecture and neutrophilic infiltration. For analysis, patients were categorized into a low histologic activity group (Nancy score, 0–2) and a high activity group (Nancy score, 3–4). Additionally, histological remission was defined as a Nancy score of 0, and histologic response was defined as a score of ≤1, with no neutrophils in the epithelium and absence of erosion or ulceration after treatment.

Endoscopic disease severity was assessed using two indices: the Mayo Endoscopic Subscore (MES) [13] and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) [14]. The MES values were classified into four stages, with MES 0 indicating inactive disease and MES 3 reflecting severe disease with ulceration and spontaneous bleeding. The UCEIS scores ranged from 0 to 8 and were grouped into four categories: remission (0–1), mild (2–4), moderate (5–6), and severe (7–8). An endoscopic response was defined as a decrease in the UCEIS score of ≥2 points during follow-up [15].

The partial Mayo (P-Mayo) score was used to assess clinical disease activity. Clinical and endoscopic parameters during follow-up were compared based on the histological response status at diagnosis to examine how the initial histological inflammation may correlate with subsequent mucosal healing and symptom control.

3. Statistical analysis

R statistical software (ver. 4.3.2; R Foundation Inc., Vienna, Austria; http://cran.r-project.org [accessed on January 9, 2023]) was used for data analyses. Categorical variables were compared using the Pearson chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. The correlation between histological and endoscopic activities was assessed using Pearson correlation coefficient. A positive value indicated a positive correlation, whereas a negative value indicated a negative correlation. Regarding the correlation coefficient magnitude, ≥0.5, 0.3 to 0.5, and 0 to 0.3 indicated strong, moderate, and weak correlations, respectively. Statistical significance was set at p<0.05.

Results

1. Clinical, endoscopic, and histologic findings at diagnosis

Table 1 shows the baseline characteristics of the participants. The mean age at diagnosis in 51 patients with UC was 34.6±13.0 years and the male-to-female ratio was 1:1.21. At diagnosis, proctitis was observed in 23 (45.1%), left-sided disease in 13 (25.5 %), and extensive disease in 15 patients (29.4 %). The mean endoscopic activity at diagnosis based on UCEIS was 5.7±1.7. The UCEIS was classified as mild, moderate, or severe in 13 (25.5%), 18 (35.3%), and 20 cases (39.2%), respectively (Table 1).

The mean Nancy score was 2.39±0.70 points. Based on the stratified Nancy score, 35 (68.6%) and 16 patients (31.4%) were included in the low and high groups, respectively. Crypt distortion was normal in five (9.8%), <5% in 18 (35.3%), <50% in 17 (33.3%), and >50% in 11 patients (21.6%). Architectural distortion was mild in 28 (54.9%), moderate in 16 (31.4%), and severe in seven patients (13.7%) (Table 2).

No significant difference in the UCEIS scores at diagnosis was observed based on histological activity (p=0.065; Table 1), and histological and endoscopic activities at diagnosis were not significantly correlated (r=0.18, p=0.200; Table 3). Meanwhile, 22 (43.1%), 16 (31.4%), and 13 patients (25.5%) had MES values at diagnosis of 1, 2, and 3, respectively, and demonstrated a significant difference according to histological activity (p=0.022; Table 1).

Treatment options included 5-aminosalicylic acid (5-ASA) in 39 (76.5%), 5-ASA suppositories in 44 (86.3%), corticosteroids in 15 (29.4%), and azathioprine/6-mercaptopurine in one patient (2.0%). None of the patients were using biologics at the time of diagnosis. No statistically significant difference in the P-Mayo scores (p=0.921) was observed between the two groups classified according to histological activity. There were no significant differences in clinical statuses, such as steroid prescription, hospitalization, and biologics administration, based on histological activity at diagnosis.

2. Histological and endoscopic findings and correlation at the first follow-up

The first endoscopic follow-up was performed at a median of 12 months after diagnosis. No significant difference in endoscopic activity was observed at diagnosis; however, a significant difference was observed between the groups at the first follow-up (p=0.026; Table 4).

Based on histological activity at the first follow-up, the low group included 40 patients (76.4%), whereas the high group decreased from 16 patients to 11 patients after treatment (Table 5). The first follow-up endoscopy revealed that 30 patients (58.8%) achieved an endoscopic response, including nine (56.2%) and 21 patients (60.0%) in the high and low groups, respectively (Table 6). According to the criteria of histological and endoscopic responses, six cases demonstrated histological and endoscopic improvement in the 1-year follow-up examination. No significant difference in the endoscopic response was observed between the groups (p=0.800; Table 6). However, the high group at diagnosis positively correlated with the UCEIS score at the first follow-up (r=0.37, p<0.001; Table 3). This correlation was maintained when we classified UCEIS into MES. A significant correlation was observed between the first follow-up MES (r=0.40, p<0.001; Table 3) and histological grades stratified according to the Nancy classification at diagnosis.

Histological activity at the last follow-up was evaluated in 24 patients, consisting of 20 patients (83.3%) in the low group, and the number of patients in the high group decreased from 16 to four after treatment. Endoscopic activities at the last follow-up revealed remission in three (12.5%), mild in eight (33.3%), moderate in six (25.0%), and severe in seven cases (29.2%).

3. Clinical outcomes according to histological activity

We compared the factors reflecting the aggravation of clinical outcomes, such as hospitalization, colectomy, and changes in therapeutic options. In our study, colectomies were not performed during the follow-up period (median, 23 months). The hospitalization rate at diagnosis did not differ between the high and low groups (6 [37.5%] vs. 12 [34.3%], p=0.800). No statistically significant difference in treatment options at diagnosis, such as steroid use (4 [25.0%] vs. 11 [31.4%], p=0.700), was observed between the two groups.

At the first follow-up examination, the hospitalization rate did not differ between the groups (3 [27.3%] vs. 9 [22.5%], p=0.700). Steroids were administered during the first follow-up in one (9.1%) and nine (22.5%) patients in the high and low groups, respectively (p=0.140). Biologics were introduced during the first follow-up in two cases (5.0%) in the low group and none in the high group.

Discussion

Despite not being adopted as a formal treatment target in UC, histologic remission is an emerging treatment target with increasing evidence [5,10]. Furthermore, high histological activity has been identified as a predictor of clinical relapse. An early study by Wright and Truelove [16] revealed that histological activity predicted the clinical relapse rate. Riley et al. [17] demonstrated that active histological inflammation in patients with endoscopically inactive UC predicted clinical relapse over a 12-month follow-up period. The histological characteristics of high relapse rates include the presence of acute inflammatory infiltrates, crypt abscesses, mucin depletion, and any breach in the surface epithelium. Basal plasmacytosis is a disease relapse predictor [18,19]. This indicates that endoscopic remission does not represent complete mucosal remission, although it demonstrates a relatively good correlation between the histological and endoscopic scoring systems [20].

However, in our study, histological and endoscopic findings at diagnosis failed to show a significant correlation. This variation could be associated with the different inclusion criteria between the groups. Riley et al. [17] enrolled patients who had a normal or slightly erythematous endoscopic appearance and had previously used 5-ASA type medications, including oral 5-ASA and suppositories. Furthermore, Bessissow et al. [19] included patients with endoscopic inactivity, and Bitton et al. [18] studied patients who achieved clinical and endoscopic remissions. Our study included patients newly diagnosed with UC and demonstrated that high histologic activity at diagnosis exhibited a positive correlation with first follow-up endoscopic activity. This indicates that elevated histological activity during diagnosis reflects inflammation severity, and as inflammation becomes more severe, the treatment response may be compromised. These results support the well-established evidence that the presence or absence of endoscopic remission is associated with long-term outcomes, as demonstrated in a few studies [21,22] and emphasized in both STRIDE I and II [4,5]. Considering these aspects, patients with high histological activity during diagnosis may remain histologically active even after appropriate management regardless of endoscopic activity. Therefore, a more active treatment approach may be required for these patients.

Unexpectedly, our study revealed a distinct perspective in contrast to earlier research. During diagnosis, endoscopic activity, represented by UCEIS or MES, did not significantly correlate with histological activity grade. However, the study yielded unpredictable results at the first follow-up. Unlike endoscopic activity at diagnosis, the first follow-up demonstrated a significant correlation with histological activity at diagnosis.

Two previous studies revealed that endoscopic findings at diagnosis may indicate an inactive state, whereas acute inflammation may still present histologically [17,20]. Furthermore, it was particularly intriguing that the histological stage at diagnosis correlated with the endoscopic results at the first follow-up. This recovery of the correlation has clinical implications, as it could provide a notion for considering initial histological activity as a predictive factor for the first follow-up endoscopic outcomes.

Previous studies have revealed that histological activity at the time of assessment is significantly associated with clinical outcomes [18,19]. Changes in histological condition after corticosteroid therapy play a crucial role in predicting clinical outcomes in the following year [23]. The possibility of remaining symptom-free in the following year is greater if the histological inflammation in UC resolves after treatment. Patients demonstrating histological remission exhibited a significantly lower rate of hospitalization or colectomy persisting for a minimum of 7 years [24]. However, our conclusions differed from those of previous studies. This reveals the limitations of endoscopic assessment. Endoscopic assessment is performed by a clinician; thus, it is inherently subjective. Furthermore, an inevitable discrepancy was observed between the histological and endoscopic diagnoses. We found no significant differences in surgery or hospitalization based on histological activity during diagnosis. However, considering factors such as the relatively short follow-up duration, a more extended follow-up period is required. Furthermore, a high degree of histological activity may indicate malignant potential. Using multivariate analysis, Rutter et al. [25] revealed that histological inflammation score was associated with colorectal cancer (odds ratio, 4.69; 95% confidence interval, 2.10–10.48; p<0.001). Although malignancy potential was not observed in our study, we believe that long-term follow-up is needed.

Histological activity assessment has several limitations, including the absence of standardization. Furthermore, we cannot be convinced that treatment options could enable us to achieve histological remission. Therefore, the STRIDE II guidelines do not yet consider it a formal target [5].

One study investigated the correlation between endoscopic and histological activities; however, it was conducted through biopsy of patients with previously confirmed UC, and the timing of assessment in each patient was not controlled [17]. Furthermore, we could not determine the clinical significance of histological activity at diagnosis. Therefore, we aimed to investigate the clinical association between histological activity at diagnosis and the endoscopic response in patients with UC.

This study had several limitations. First, the sample size was relatively small and the follow-up period was limited to approximately 1 year, which may have constrained our ability to observe long-term clinical outcomes or conduct robust multivariable analyses. Second, although we observed an association between histological and endoscopic activities, the influence of treatment regimens and other potential confounding variables could not be fully accounted for because of the retrospective design. Third, although we categorized histological activity using the Nancy index into low and high groups for clinical clarity, this binary grouping has not been externally validated.

Nevertheless, this study offers meaningful insights. We evaluated the histological, endoscopic, and clinical disease activities at diagnosis, first follow-up, and final follow-up, enabling us to capture early disease trajectories. By anchoring our assessment to the point of diagnosis, we explored the prognostic implications of histological activity from the outset. Moreover, by applying practical stratification using the Nancy index, our findings suggest that histologic activity at diagnosis not only reflects concurrent endoscopic inflammation but also predicts short-term clinical and endoscopic outcomes. These results support the potential utility of histological assessment in routine clinical decision making.

Histological activity according to the Nancy histological index revealed no significant correlation with endoscopic activity as assessed by UCEIS and MES at diagnosis. However, UCEIS and MES stratified at the first follow-up correlated with the histological activity at diagnosis. The group with low histological activity at diagnosis demonstrated a higher probability of endoscopic response. A prospective study with a larger number of patients is warranted; however, more active care should be indicated for patients with high histological activity at diagnosis.

Article information

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Acknowledgments

Thank MJ Gu for histologic diagnosis and grading.

Funding

This study was supported by 2021 Yeungnam University Research Grant.

Author contributions

Conceptualization: KOK, BIJ; Data curation, Formal analysis: MCK; Funding acquisition: KOK; Writing-original draft: KOK, JSY; Writing-review & editing: KOK, JSY, BIJ

Fig. 1.

Flow chart of enrollment of patients. UC, ulcerative colitis.

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References

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