
==== Front
Int J Colorectal Dis
Int J Colorectal Dis
International Journal of Colorectal Disease
0179-1958
1432-1262
Springer Berlin Heidelberg Berlin/Heidelberg

39302470
4723
10.1007/s00384-024-04723-7
Research
Clinical and histological impact of diffuse inflammation at pouchoscopy
http://orcid.org/0000-0001-5184-8819
Toritani Kenichiro 1
http://orcid.org/0000-0002-3407-7693
Kimura Hideaki hkim@yokohama-cu.ac.jp

1
Goto Koki 1
Matsubayashi Mao 1
http://orcid.org/0000-0003-3083-9600
Kunisaki Reiko 1
http://orcid.org/0000-0002-7187-3664
Watanabe Jun 2
http://orcid.org/0000-0002-3251-3658
Ishibe Atsushi 3
Otani Masako 4
http://orcid.org/0000-0001-5520-8114
Endo Itaru 3
1 https://ror.org/03k95ve17 grid.413045.7 0000 0004 0467 212X Inflammatory Bowel Disease Center, Yokohama City University Medical Center, 4-57, Urafune-Cho, Minami-Ku, Yokohama, 232-0024 Japan
2 https://ror.org/03k95ve17 grid.413045.7 0000 0004 0467 212X Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
3 https://ror.org/0135d1r83 grid.268441.d 0000 0001 1033 6139 Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
4 https://ror.org/04ds03q08 grid.415958.4 0000 0004 1771 6769 Department of Pathology, International University of Health and Welfare Mita Hospital, Tokyo, Japan
20 9 2024
20 9 2024
2024
39 1 14612 9 2024
© The Author(s) 2024
2024
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Purpose

The anatomical location of inflammation in and around the ileal pouch affects the pouch survival rate, and diffuse inflammation has poor pouch survival rates. We aimed to clarify the symptoms and histological findings of diffuse inflammation of the pouch.

Methods

We evaluated the symptoms, treatment, and histological findings according to the endoscopic phenotypes of diffuse inflammation, focal inflammation, and normal as the pouch body phenotype and afferent limb involvement, inlet involvement, cuffitis, and fistula as the peripheral findings.

Results

Of the 318 pouchoscopies, 47 had diffuse inflammation, 201 had focal inflammation, and 70 were normal. Symptomatic patients had diffuse inflammation more frequently (46.8%) than focal inflammation (13.4%) and normal (14.2%), with no difference between focal inflammation and normal. Antibiotics and steroids were higher rate administered in cases of diffuse inflammation, but not in cases of focal inflammation or in normal cases. Histological inflammation, inflammatory bowel disease (IBD)–specific finding, and colonic metaplasia showed severity in the order of diffuse inflammation > focal inflammation > normal. The number of peripheral inflammatory findings overlapped in the following order: diffuse inflammation > focal inflammation > normal. The number of symptomatic patients increased as the number of peripheral inflammatory findings increased.

Conclusion

Pouches with diffuse inflammation are more symptomatic, have a higher use of therapeutic agents, and have more severe histological inflammation, IBD-specific finding, and colonic metaplasia accompanying peripheral inflammatory findings than the other groups. The higher the overlap of inflammatory findings in the surrounding tissues, the more symptomatic the patients will appear.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00384-024-04723-7.

Keywords

Ulcerative colitis
Ileal pouch
Pouchitis
Diffuse inflammation
Chicago classification
issue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2024
==== Body
pmcIntroduction

Inflammation of the pouch (pouchitis) is a common complication of ileal pouch-anal anastomosis (IPAA). The pouchitis disease activity index (PDAI) and pouchitis activity score (PAS) are widely used in the diagnosis and severity of pouchitis [1, 2]; however, the long-term impact and prognosis of pouchitis are not well understood.

Recently, the prognosis of ileal pouches has been shown to differ depending on the site of inflammation [3]. The Chicago classification focuses on the inflammation site of the ileal pouch, and patients with diffuse inflammation in the pouch and patients with overlapping classifications have low pouch survival rate [4]. Reports based on the Chicago classification have been published in recent years [5, 6]. However, the clinical symptoms and histological findings of Chicago classification in these patients are not clear, and it is unclear why diffuse inflammation have a poor long-term prognosis.

The present study therefore clarified the clinical and histological effects of the endoscopic phenotype of the diffuse inflammation in the pouch.

Materials and methods

Study population and material

The study population and materials are shown in Fig. 1. We enrolled 187 consecutive patients who underwent initial surgical resection of ulcerative colitis (UC) at Yokohama City University Medical Center in Japan, a tertiary referral IBD center, from January 2012 to December 2018. The exclusion criteria were as follows: (1) no ileal pouch construction; (2) no postoperative pouchoscopy; and (3) an insufficient assessment or biopsy at pouchoscopy. The study adhered to the recommendations of the Equator Network (The Strengthening the Reporting of Observational Studies in Epidemiology Statement).Fig. 1 Outline of patient selection. UC, ulcerative colitis; AL, afferent limbs

The indications, technique, and the procedure for surgery were as previously reported [7–9]. In brief, stapled IPAA was performed in patients whose surgical indications were severe or refractory colitis, and proctocolectomy with hand-sewn IPAA was performed in patients whose surgical indications were cancer or dysplasia. A 12-cm-long ileal J-pouch was constructed for all patients. Pouchoscopy was also performed routinely every 2 years as previously reported [7]. Patients were referred every 3 months or when symptomatic. Pouchitis was diagnosed by the clinician based on symptoms and the recent endoscopic findings, and an antibiotic was prescribed. If the patient was resistant to antibiotics, steroid or inflammatory bowel disease (IBD) drugs were prescribed in agreement with the patient. Probiotics and antidiarrheal medications were prescribed based on the patient’s wishes and the defecation condition.

Endoscopic definition of Chicago classification

The anatomical lesion at pouchoscopy was evaluated based on the Chicago classification (Fig. 2) [4]. In summary, the oral side of the pouch was defined as the afferent limb (AL), the inflow portion into the pouch as the inlet (IL), and the contralateral side of the AL as the tip of J (Tip). The oral half of the pouch was defined as proximal pouch (PP), the anal half as distal pouch (DP), and the area from the dentate line to the ileal pouch-anal anastomosis as the rectal cuff (RC). Inflammation in these lesions was also evaluated based on the Chicago classification [4], and endoscopic inflammatory findings (edema, granularity, friability, loss of vascular pattern, mucous exudate, and ulceration) were evaluated according to the PDAI [1]. Diffuse inflammation was defined as two or more inflammatory findings at all pouch sites (Tip, PP, and DP). Normal was defined as no inflammation at any sites of the pouch, and focal inflammation was defined as neither normal nor diffuse inflammation (Fig. 3). Peripheral findings of the pouch were classified as AL involvement if one or more inflammatory findings were found in the AL, IL involvement if one or more inflammatory findings were found in the IL, cuffitis if one or more inflammatory findings were found in the RC, and fistulas if there was fistula at any site 6 months postoperatively (Fig. 4). Based on this definition, pouches were classified as having diffuse inflammation, normal, or focal inflammation, and the peripheral findings around the pouch (AL involvement, IL involvement, cuffitis, and fistula) were considered accompanying findings (peripheral inflammatory findings). Two physicians (H.K. and K.T.) specializing in IBD and with more than 5 years of experience of IBD and more than 100 pouchoscopy cases checked the colonoscopy’s report.Fig. 2 Anatomical lesion within and around the pouch

Fig. 3 Definition of the classification of the pouch findings. Diffuse inflammation was defined as fulfilling all of the following criteria: Tip, PDAI-E ≥ 2; PP, PDAI-E ≥ 2; and DP, PDAI-E ≥ 2. Normal was defined as fulfilling all of the following criteria: Tip, PDAI-E = 0; PP, PDAI-E = 0; and DP, PDAI-E = 0. Focal inflammation was defined as neither normal nor diffuse inflammation. PP, proximal pouch; DP, distal pouch; PDAI-E, pouchitis disease activity index endoscopic sub-score

Fig. 4 Definition of the classification of the peripheral findings. AL, afferent limbs; IL, inlet; PDAI-E, pouchitis disease activity index endoscopic sub-score

Clinical and histopathological evaluation

The clinical evaluation was performed using clinical reports. All patients were surveyed for stool frequency, medication status, and clinical symptoms according to the PDAI clinical subscore (PDAI-C) at the time of pouchoscopy [1].

Biopsies were obtained from the most endoscopically inflamed sites in each segment (AL, PP, and DP). Hematoxylin and eosin-stained histological sections from biopsy specimens of the AL, PP and DP were re-examined. The histopathological evaluation was performed as described in our previous report [9]. In brief, histological inflammation was evaluated using the PDAI histology subscore (PDAI-H) [1], IBD-specific findings (basal plasmacytosis, crypt distortion, crypt atrophy, and paneth cell metaplasia) as the IBD Score (SIBD) [10], colonic metaplasia (villus atrophy and crypt hyperplasia) as the colonic metaplasia scores (CMS) [11], and presence of granuloma as one of the characteristics of Crohn’s disease (CD).

Statistical analyses

Descriptive statistics were reported as the median and interquartile range for continuous variables and frequencies and percentiles for categorical variables. Differences between continuous variables were tested using the Mann–Whitney U test, and categorical variables were tested using chi-squared test. P values of < 0.05 were considered statistically significant, but the Bonferroni method was used when multiple comparisons were conducted (three group comparison, P values of < 0.017 were considered statistically significant). Statistical analyses were performed using the SPSS software program (version 25.0, SPSS Inc., Chicago, IL, USA).

Results

A total 187 patients and 318 pouchoscopies (until March 2020) were enrolled. The characteristics of the study population are presented in Supplementary Tables S1 and S2. The postoperative diagnosis were UC in 186 patients and indeterminate colitis in 1 patient. The mean follow-up period was 4.7 (interquartile range: 3.3–6.6) years. No postoperative oncogenesis was observed in any patient during the follow-up period. Pouch failure was experienced in 1 case (0.5%). Pouchitis was observed in 35 cases (18.7%) during the follow-up period, and 59 cases (18.6%) were symptomatic of pouchitis at the time of pouchoscopy.

Symptoms and treatment according to the pouch phenotype

Symptoms and treatment between diffuse inflammation, focal inflammation. and the normal are listed in Table 1. The proportion of symptomatic patients with diffuse inflammation was significantly higher (46.8%) than that with focal inflammation (13.4%) and normal (14.2%), but there was no marked difference between the proportions with focal inflammation and those with normal groups. The PDAI-C was also significantly higher in diffuse inflammation than in focal inflammation and normal. Among these symptoms, increased stool frequency and fecal urgency were significantly more common in patients with diffuse inflammation than in others. Regarding medication at pouchoscopy, there were no marked differences in the rates of probiotics, berberine chloride medication, and IBD drugs among the three groups. However, the use of loperamide was significantly lower in normal than in focal inflammation, and the use of antibiotic and steroid was significantly higher in diffuse inflammation than in other groups. Table 1 The symptoms and treatment between the phenotypes of the pouch

Factors	Diffuse inflammation
(n = 47)	Focal inflammation
(n = 201)	Normal
(n = 70)	p Value	
D/ F	D/ N	F/ N	
Age at pouchoscopy (year)*	44 (27–57)	39 (27–52)	44 (28–57)	0.360	0.969	0.284	
Duration of pouch usage (year)*	1.4 (1.2–3.4)	2.3 (1.2–3.6)	1.4 (1.3–2.7)	0.079	0.898	0.027	
PDAI clinical subscore*	0 (0–1)	0 (0–0)	0 (0–0)	 < 0.001	 < 0.001	0.912	
  PDAI clinical subscore ≥ 1	22 (46.8)	27 (13.4)	10 (14.2)	 < 0.001	 < 0.001	0.858	
  Increased stool frequency	11 (23.4)	14 (7.0)	4 (5.7)	0.001	0.001	0.526	
  Bleeding	4 (8.5)	12 (5.9)	2 (2.9)	0.529	0.180	0.317	
  Fecal urgency	14 (29.7)	11 (5.4)	5 (7.1)	 < 0.001	0.001	0.597	
  Fever	2 (4.2)	0 (0.0)	0 (0.0)	0.003	0.084	n.a	
Stool frequency*	8 (7–10)	7 (5–10)	7 (5–10)	0.012	0.020	0.956	
Medication							
  Probiotics	34 (72.3)	148 (73.6)	49 (70.0)	0.857	0.785	0.557	
  Berberine chloride	33 (70.2)	137 (68.1)	42 (60.0)	0.785	0.259	0.214	
  Loperamide	15 (31.9)	60 (29.9)	10 (14.3)	0.781	0.023	0.010	
  Antibiotic	7 (14.9)	9 (4.5)	1 (1.4)	0.009	0.005	0.244	
  Steroid	5 (10.6)	3 (1.5)	1 (1.4)	 < 0.001	0.027	0.970	
  IBD drugs	1 (2.1)	2 (1.0)	0 (0.0)	0.523	0.220	0.402	
PDAI	9 (7–11)	5 (4–6)	2 (1–3)	 < 0.001	 < 0.001	 < 0.001	
  PDAI ≥ 7	38	37	0	 < 0.001	 < 0.001	 < 0.001	
Modified PDAI	4 (3–5)	2 (2–2)	0 (0–0)	 < 0.001	 < 0.001	 < 0.001	
  Modified PDAI ≥ 5	19	9	0	 < 0.001	 < 0.001	 < 0.001	
Values in parentheses are percentages, unless indicated otherwise

*Values are median (interquartile range)

PDAI pouch disease activity index, IBD drugs inflammatory bowel disease drugs including amino salicylates, immunosuppressor, immunomodulators, and biologics

The PDAI score was significantly higher in the diffuse inflammation group, following by the focal inflammation group and then the normal group, and the same trend was observed for the positive rate of PDAI and modified PDAI.

Symptoms and treatment according to the number of the peripheral inflammatory findings

The symptoms and treatment according to the number of peripheral inflammatory findings were shown in Table 2. Cases with multiple peripheral inflammatory finding were more common in diffuse inflammation and less in normal, whereas cases with no peripheral inflammatory findings were more common in normal and less common in diffuse inflammation. Details of regarding the duplication of the pouch phenotype and peripheral inflammatory findings are shown in Supplementary Table S3. The number of symptomatic patients and PDAI-C increased in relation to the number of peripheral inflammatory findings. The frequency of defecation was significantly higher in pouches with multiple peripheral inflammatory findings than in those with no peripheral inflammation. The use of antibiotics was significantly higher in the multiple peripheral inflammatory finding group than in the single and no peripheral inflammatory findings groups. Table 2 The symptoms and treatment between the number of the peripheral inflammatory findings

Factors	Multiple peripheral inflammation
(n = 41)	Single peripheral inflammation
(n = 135)	No
peripheral inflammation
(n = 142)	p Value	
M/ S	M/ N	S/ N	
Age at pouchoscopy (year)*	42 (26–49)	42 (26–55)	42 (30–53)	0.609	0.577	0.967	
Duration of pouch usage (year)*	1.7 (1.2–3.9)	1.6 (1.2–3.5)	1.5 (1.2–3.4)	0.590	0.537	0.927	
Phenotypes of the pouch							
  Normal	0 (0.0)	17 (12.6)	53 (37.3)	 < 0.001	 < 0.001	 < 0.001	
  Focal inflammation	13 (31.7)	101 (74.8)	87 (61.3)	
  Diffuse inflammation	28 (68.3)	17 (12.6)	2 (1.4)	
PDAI clinical sub-score	0 (0–2)	0 (0–0)	0 (0–0)	 < 0.001	 < 0.001	0.014	
 PDAI clinical sub-score ≥ 1	19 (46.3)	27 (20.0)	13 (9.2)	0.001	 < 0.001	0.010	
   Increased stool frequency	13 (31.7)	8 (5.9)	7 (4.9)	 < 0.001	 < 0.001	0.662	
   Bleeding	6 (14.6)	7 (5.1)	5 (3.5)	0.043	0.009	0.566	
   Fecal urgency	13 (31.7)	13 (9.6)	4 (2.8)	 < 0.001	 < 0.001	0.020	
   Fever	1 (2.4)	1 (0.7)	0 (0)	0.369	0.064	0.308	
Stool frequency	9 (7–10)	7 (6–10)	6 (5–10)	0.051	0.001	0.025	
Medication							
   Probiotics	31 (75.6)	106 (78.5)	94 (66.2)	0.694	0.254	0.022	
   Berberine chloride	29 (70.7)	100 (74.1)	83 (58.5)	0.672	0.155	0.006	
   Loperamide	15 (36.6)	40 (29.6)	30 (21.1)	0.400	0.043	0.104	
 Antibiotic	10 (24.3)	3 (2.1)	4 (2.8)	 < 0.001	 < 0.001	0.753	
 Steroid	2 (4.9)	4 (2.9)	3 (2.1)	0.554	0.339	0.652	
 IBD drugs	1 (2.4)	2 (1.5)	0 (0.0)	0.678	0.062	0.145	
Values in parentheses are percentages, unless indicated otherwise

*Values are median (interquartile range)

AL, afferent limbs, PP proximal pouch, DP distal pouch, PDAI pouchitis disease activity index, IBD drugs inflammatory bowel disease drugs including amino salicylates, immunosuppressor, immunomodulators, and biologics, M multiple peripheral inflammation, S single peripheral inflammation, N no peripheral inflammation

Endoscopic and histological inflammation according to the pouch phenotype

Endoscopic and histological inflammation according to pouch phenotype are shown in Fig. 5 and Supplementary Figure S1. Endoscopic and histological inflammation in the pouch were significantly higher in the diffuse inflammation group, followed by the focal inflammation and then normal group. The SIBD and CMS according to the pouch phenotype were shown in Supplementary Figures S2 and S3. The IBD score and CMS in the pouch were significantly higher in the diffuse inflammation group, followed by the focal inflammation and then normal group. None of the specimens showed granulomas.Fig. 5 Histological inflammation according to the pouch phenotype. Histological inflammation of the pouch body is in the order of diffuse inflammation > focal inflammation > normal. PDAI-H of diffuse inflammation is 1 (1–3) et al., 4 (3–5) at PP, and 4 (3–5) at DP. PDAI-H of focal inflammation is 0 (0–1) et al., 2 (1–3) at PP, and 2 (1–3) at DP. PDAI-H of normal is 0 (0–1) et al., 1 (0–2) at PP, and 2 (1–3) at DP. PDAI-H, pouchitis disease activity index histological sub-score; AL, afferent limbs; PP, proximal pouch; DP, distal pouch

Discussion

We evaluated 187 patients and 318 pouchoscopies and found that pouches with diffuse inflammation were more symptomatic, with a higher use of therapeutic agents and severe endoscopic and histological inflammation accompanying peripheral inflammatory findings than in the other groups.

Diffuse inflammation in the pouch is associated with a high risk of pouch excision [4], and it causes a low Cleveland Global Quality of Life score [5]. We also found that symptoms characteristic of pouchitis, such as increased stool frequency, stool urgency, and fever, were often observed in patients with diffuse inflammation of the pouch, and the decreased quality of life associated with these symptoms may be linked to pouch failure. Histological inflammation and colonic metaplasia (villus atrophy and crypt hyperplasia) in the pouch were high in cases of diffuse inflammation. Severe inflammation and villus atrophy (type C mucosa) have been reported to be risk factors for carcinogenesis [12], and carcinogenesis in the pouch leads to pouch failure. However, in a multicenter surveillance pouchoscopy study using the same risk classification, no neoplasia was found at follow-up in the pouch with type C mucosa [13]. We found many cases of high inflammation with colonic metaplasia, including villous atrophy in diffuse inflammation, but no case of carcinogenesis. In the latest consortium, the relationship between pouch inflammation and carcinogenesis was unclear [14]. Treatment of asymptomatic patients with diffuse inflammation are controversial.

Cases of focal inflammation, i.e., pouches with localized inflammation, had fewer symptoms than cases of diffuse inflammation, but the clinical symptoms did not differ markedly from normal. Focal inflammation may thus not contribute to the clinical symptoms. Loperamide, a powerful antidiarrheal agent, was used more in focal inflammation than in normal cases, and inflammation was more concentrated in the distal pouch than the proximal pouch and tips in focal inflammation. Some focal inflammation may be an adaptive change to fecal stasis [15]. IBD-specific findings showed that over half of the diffuse inflammation pouch bodies had definite IBD (IBD score ≥ 2), whereas over half of the focal inflammation pouch bodies had unknown or non-IBD (IBD score ≥ 0). Therefore, these groups may be distinguished from those with pouchitis associated with IBD pathogenesis [14].

Normal cases with no inflammation in the pouch were associated with the highest rate of pouch survival rate [4]. In our study, 14.2% of cases had some pouchitis symptoms. Surrounding inflammation or structural disease may cause symptoms of pouchitis when the pouch is not inflamed [16]. If there are no abnormality in these cases, functional pouch disorders such as irritable pouch syndrome, proctalgia fugax, and neuropathic pain may be considered [17]. Patients with functional pouch disorder may benefit from antidiarrheal agents, dietary modifications, biofeedback therapy, antispasmodics, and tricyclic antidepressants [18].

Peripheral inflammatory findings, and inflammatory findings outside of the pouch, were classified in the same category as findings within the pouch in the Chicago classification. We focused on the impact of diffuse inflammation within the pouch; therefore, we categorized the peripheral inflammatory findings as accompanying findings. Peripheral inflammatory findings were more common in diffuse inflammation, the number of symptomatic patients increased in proportion to the number of peripheral inflammatory findings, and the use of antibiotic was higher in patients with multiple peripheral inflammatory findings than in the other patients.

Peripheral inflammatory findings were classified as AL involvement, IL involvement, cuffitis, and fistula, as in previous reports. AL and IL involvement are both pre-pouch ileitis, and the symptoms of pre-pouch ileitis are not specific [19]. Pre-pouch ileitis has been reported in cases diagnosed with CD or CD like pouch, and these cases are resistant to treatment and have poor prognostic factors [3, 19]. However, pre-pouch ileitis can also be caused by systemic inflammatory reactions similar to duodenitis and extraintestinal complications, backwash ileitis from diffuse pouchitis, ischemia, use of non-steroidal anti-inflammatory drugs, and structural complications in addition to CD [14]. In our data, granulomas were not observed in all cases, and about half of the cases were complicated by diffuse inflammation, suggesting that many cases may not have been inflammation due to CD pathology. Cuffitis shows inflammation in the retained rectal mucosa, with symptoms similar to those of pouchitis, such as bleeding, increased stool frequency, and fecal urgency. Although classic cuffitis is secondary to residual UC in rectal tissue, non-classic cuffitis is defined as inflammation from any other cause [20]. As shown in Supplementary Table S3, cuffitis was more common with diffuse inflammation and focal inflammation than with normal cases. Therefore, inflammation in some cases with a residual rectum may be related to inflammation of the pouch. Hand-sewn IPAA completely removes the rectal mucosa and theoretically cannot cause cuffitis (cuffitis in this study was Stapled IPAA/hand-sewn IPAA: 46.2%/0.0%, data not shown in the results). Because stapled IPAA is a simple procedure and has good anorectal function [7], the indication for hand-sewn or stapled IPAA should be examined based on its risks and benefits. Fistulas were found in all three groups, and there was no significant difference among them. Late-onset fistula, i.e., all cases except early-onset fistula (anastomosis leakage), which was also excluded from the fistula cases in this study, is considered a suspicious finding for CD pouch and CD-like pouch [3]. Fistulas due to cryptoglandular infection from the dentate line are more frequently observed than those from the pouch [21], and this frequency has been found to be higher in UC patients than in healthy controls [22]. In our experience, over half of fistulas occur from the dentate line, and it should be noted that not all post-IPAA fistulas are associated with CD.

Several limitations associated with the present study warrant mention. First, it was a single-center, retrospective study. Because only routine endoscopies are performed for surveillance, endoscopies are not performed when the symptoms are severe. In addition, cases with insufficient assessment, imaging findings, and tissue evaluation were excluded, so cases with structural complications, such as stenosis, may have been among the excluded cases. Second, the short follow-up period led to resection of the pouch in only one case. Long-term follow-up is required to investigate why pouch resection is often performed in patients with diffuse inflammation.

Conclusion

Pouches with diffuse inflammation are more symptomatic, have a higher use of therapeutic agents, and have more severe endoscopic and histological inflammation accompanying peripheral inflammatory findings than the other groups. The greater the overlap of inflammatory findings in the surrounding tissues, the more symptomatic patients will appear. These symptoms, histological findings, and treatment needs may explain the poor prognosis of pouches with diffuse inflammation.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (DOCX 33 KB)

Supplementary file2 (DOCX 322 KB)

Acknowledgements

The authors gratefully acknowledge the patients who participated in the study.

Author contribution

K.T. and H.K. contributed to the study design. All of the authors contributed to the data collection and interpretation. H.K. and K.T. evaluated endoscopic findings. M.O. and K.T. evaluated histopathological findings. All of the authors contributed to the writing or review of the report and approved the final version.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval

The study protocol was approved by the Ethical Advisory Committee of Yokohama City University Graduate School of Medicine (registration no. (B210400067)).

Consent to participate

For this type of study, informed consent is not required.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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