Abstract
Background
Patients with inflammatory bowel disease (IBD) who undergo proctocolectomy with ileal pouch–anal anastomosis may develop pouchitis. We previously proposed a novel endoscopic classification of pouchitis describing 7 phenotypes with differing outcomes. This study assessed phenotype transitions over time.
Methods
We classified pouch findings into 7 main phenotypes: (1) normal, (2) afferent limb (AL) involvement, (3) inlet (IL) involvement, (4) diffuse, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) pouch-related fistulas noted more than 6 months after ileostomy takedown. Among 2 endoscopic phenotypes, the phenotype that was first identified was defined as the primary phenotype, and the phenotype observed later was defined as the subsequent phenotype.
Results
We retrospectively reviewed 1359 pouchoscopies from 426 patients (90% preoperative diagnosis of ulcerative colitis). The frequency of primary phenotype was 31% for AL involvement, 42% for IL involvement, 28% for diffuse inflammation, 72% for focal inflammation, 45% for cuffitis, 18% for pouch-related fistulas, and 28% for normal pouch. The most common subsequent phenotype was focal inflammation (64.8%), followed by IL involvement (38.6%), cuffitis (37.8%), AL involvement (25.6%), diffuse inflammation (23.8%), normal pouch (22.8%), and pouch-related fistulas (11.9%). Subsequent diffuse inflammation, pouch-related fistulas, and AL or IL stenoses significantly increased the pouch excision risk. Patients who achieved subsequent normal pouch were less likely to have pouch excision than those who did not (8.1% vs 15.7%; P = .15).
Conclusions
Pouch phenotype and the risk of pouch loss can change over time. In patients with pouch inflammation, subsequent pouch normalization is feasible and associated with favorable outcome.
Keywords: pouch outcome, pouchitis, Chicago classification of pouchitis, pouch normalization
Key Messages.
What is already known?
While we previously proposed a novel endoscopic classification of pouchitis describing 7 distinct phenotypes with different clinical outcomes in inflammatory bowel disease, it is still unclear how each phenotype changes over time.
What is new here?
We found that pouch phenotypes can change over time, and subsequent development of diffuse inflammation, pouch-related fistulas, and afferent limb/inlet stenoses significantly worsens pouch outcomes, whereas pouch normalization is associated with favorable outcomes.
How can this study help patient care?
We suggest that patients having these subsequent phenotypes with poor prognosis may require intensive treatments, and pouch endoscopic normalization can be a therapeutic target.
Introduction
Total proctocolectomy with ileal pouch–anal anastomosis (IPAA) is a standard surgical approach for inflammatory bowel disease (IBD). However, pouchitis, a novel inflammatory condition of this new anatomy, can develop in up to 70% of patients with IPAA.1 Approximately 20% of these patients experience low or poor quality of life attributed to their pouch, and the rate of pouch failure resulting in pouch excision or diverting loop ileostomy is reported to be up to 10%.1,2 Hence, to maintain a healthy pouch and improve pouch outcomes, clinical and endoscopic monitoring of the patient with a pouch is important. However, there is significant heterogeneity of pouch inflammation and limited information about pouch outcomes over time that guide therapeutic interventions.
We previously proposed the Chicago classification of pouchitis of 7 endoscopic pouch phenotypes and found that patients with diffuse inflammation of the pouch body, inlet (IL) stenosis, or cuffitis had significant risks of pouch loss.3 Notably, diffuse inflammation was an independent phenotype associated with pouch excision (hazard ratio, 2.7; 95% confidence interval [CI], 1.3-5.4).3 Therefore, our endoscopic pouch classification can be used to stratify patients at high risk of pouch loss. However, the potential for pouch phenotypes to change over time was not described.
There have been few studies focusing on the transition of pouchitis phenotypes, and although endoscopic healing in ulcerative colitis (UC) and Crohn’s disease (CD) is associated with improved clinical outcomes,4 there are no data on the predictive value of endoscopic healing of the pouch on its outcomes.
Here, we assessed transition of pouch phenotypes over time and assessed the influence of phenotype transition and pouch normalization on pouch outcomes.
Methods
We utilized our previously described pouch database3 and conducted a retrospective cohort study of IBD patients treated by total proctocolectomy with IPAA in J-pouch configuration who subsequently underwent pouchoscopies at the University of Chicago between June 1997 and December 2019. The Institutional Review Board of the University of Chicago approved this study (#16-0061, #15573A).3
Endoscopic Findings
A standardized operating protocol for pouchoscopies is used at our center, which includes images and reported findings by anatomic segment of the pouch and perineal areas. Using these reports, we characterized the inflammatory findings including erythema/edema, erosions/friability, ulceration, stenosis, granularity, and loss of vascular pattern. Findings of perianal, anal, or perineal disease included anal fissures, fistulas, skin tags, or hemorrhoids.
Data Acquisition
We assessed all available reports of pouchoscopies after ileostomy takedown and characterized pouch phenotypes using the endoscopy report and images. If the endoscopic description was not explicit or the findings were not noted, the endoscopy images were used to report the findings. If the endoscopic description and images were not available, we assigned these data as “not available.” We classified the pouches into 7 main pouch phenotypes based on the anatomic location of abnormalities: (1) normal, (2) afferent limb (AL) involvement, (3) IL involvement, (4) diffuse inflammation of the pouch body, (5) focal inflammation of the pouch body, (6) cuffitis, and (7) J pouch with fistulas (in this analysis, labeled “pouch-related fistulas”).3 A normal pouch was defined as the pouch without any abnormal endoscopic findings at all anatomical locations of the J pouch, anastomosis, cuff, anal canal, and perianal area and any type of fistulas. AL or IL involvement was defined as a patient with any type of endoscopic inflammation in the AL or IL, respectively. In this analysis, pouchitis was defined as 1 or more endoscopic findings of inflammation in any of the tip, proximal, or distal pouch. Diffuse inflammation of the pouch body was defined as 2 or more endoscopic findings of inflammation in all anatomical locations of the pouch body (the tip, proximal, and distal pouch). Focal inflammation of the pouch body was defined as pouchitis that did not meet the criteria for diffuse inflammation of the pouch body. Cuffitis was defined as a pouch with any type of endoscopic inflammation in the rectal cuff. Pouch-related fistulas included pouches with any type of fistulas arising from the pouch, the rectal cuff, or the anal/perineal area noted by pouchoscopy or other imaging studies including pouchogram, computed tomography, or magnetic resonance imaging after 6 months from ileostomy takedown, in order to exclude fistulas that occur temporally proximate to surgery as a technical complication.5
We retrospectively reviewed electronic medical records and collected the following data: body mass index (<25 kg/m2 vs ≥25 kg/m2), smoking status, sex, race, age at IBD diagnosis and colectomy (<18 years vs ≥18 years), primary sclerosing cholangitis, family history of IBD, disease duration until colectomy (<7 vs ≥7 years), diagnosis before and after colectomy, indication for surgery, preoperative Clostridioides difficile infection, disease extent according to Montreal classification (E1, proctitis; E2, left-sided disease; E3, extensive disease),6 technique of IPAA (stapled vs hand sewn), number of stages of IPAA (3 vs 1 or 2), postoperative complications, and pre- and postoperative therapies (Table S1). Data were collected using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at the University of Chicago.7
Statistical Analysis
We identified scope date when each phenotype was initially observed. Among 2 endoscopic phenotypes, the phenotype that was first identified was defined as the primary phenotype, and the phenotype observed later was defined as the subsequent phenotype. If the 2 phenotypes were identified at the same scope date or there were no follow-up scopes, the cases were excluded in the analysis. For each primary phenotype, event-free survival (EFS) for a subsequent phenotype was estimated with a Kaplan-Meier curve. EFS was assessed from the scope date when a primary phenotype was identified to the date when a subsequent phenotype was described. To assess the pouch normalization, we used the last date of scopes that identified a subsequent normal pouch. If no subsequent phenotypes were observed, the date of the last scope was used instead of the date of subsequent phenotypes. Fisher’s exact test was used for a univariate analysis to identify factors contributing to subsequent pouch phenotype. Logistic regression analysis was also performed as a multivariate analysis including univariate variables with a P value <.05. Due to the limited number of events, we included <5 variables in this analysis to avoid overfitting. We prioritized variables that were more likely to be related to phenotype transition or pouch outcomes (eg, primary pouch phenotypes or patients’ demographics) and did not include postoperative treatment because it was likely driven by severe subsequent phenotypes. P values <.05 were considered statistically significant. Data were analyzed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),8 a graphical user interface for R (version 2.13.0; R Foundation for Statistical Computing).
Results
We identified 426 IBD patients treated by total proctocolectomy and IPAA in J-pouch configuration, and their demographic characteristics are summarized in Table S1.3 Among these patients, 240 (56.3%) were men and 383 (89.9%) were White. Patients had a preoperative diagnosis of UC (n = 384 [90.1%]), indeterminate colitis (n = 34 [8.0%]), or Crohn’s colitis (n = 7 [1.6%]). We evaluated a total of 1359 pouchoscopies (mean 3.2 pouchoscopies per patient) with a mean follow-up of 10.9 years. The overall rate of pouch failure was 11.3% (48 patients). Four patients were excluded from our study due to data not available.
Phenotype Transition and Pouch Outcomes
Among 422 cases, the frequency of primary phenotype was 31% for AL involvement, 42% for IL involvement, 28% for diffuse inflammation, 72% for focal inflammation, 45% for cuffitis, 18% for pouch-related fistulas, and 28% for normal phenotype. Among primary pouch-related fistulas, perianal fistula (60%) was dominant (Table S2). Kaplan-Meier curves of the transition in pouch phenotypes show the overall rate of subsequent phenotypes in patients by primary phenotype (Table 1Figure S1). The most common subsequent phenotype from any primary phenotype was focal inflammation (64.8%), followed by IL involvement (38.6%), cuffitis (37.8%), AL involvement (25.6%), diffuse inflammation (23.8%), normal pouch (22.8%), and pouch-related fistulas (11.9%) (Table 1). The most common type of subsequent pouch-related fistulas was perianal fistula (56%), followed by rectovaginal/anovaginal fistula (22%) and fistula from the pouch (16%) (Table S2).
Table 1.
The rates of subsequent phenotypes in each primary phenotype.
| Subsequent AL involvement | Subsequent IL involvement | Subsequent diffuse inflammation | Subsequent focal inflammation | Subsequent cuffitis | Subsequent fistulas (≥6 mo) | Subsequent normal pouch | |
|---|---|---|---|---|---|---|---|
| Primary AL involvement | 66.7 (20/30) | 38.1 (24/63) | 88.0 (22/25) | 40.7 (24/59) | 18.6 (16/86) | 15.4 (14/91) | |
| Primary IL involvement | 28.3 (15/53) | 26.8 (19/71) | 80.0 (32/40) | 35.6 (26/73) | 14.3 (15/105) | 15.4 (18/117) | |
| Primary diffuse inflammation | 32.1 (17/53) | 57.9 (22/38) | 69.4 (34/49) | 40.9 (18/44) | 20.2 (17/84) | 14.0 (12/86) | |
| Primary focal inflammation | 24.8 (41/165) | 40.4 (65/161) | 26.0 (52/200) | 37.7 (57/151) | 9.1 (18/198) | 24.8 (52/210) | |
| Primary cuffitis | 25.5 (28/110) | 38.8 (38/98) | 24.8 (26/105) | 56.6 (30/53) | 12.9 (17/132) | 19.8 (26/131) | |
| Primary fistulas (≥6 mo) | 22.6 (12/53) | 44.4 (24/54) | 19.6 (11/56) | 67.9 (36/53) | 32.7 (18/55) | 6.2 (4/65) | |
| Normal | 20.8 (15/72) | 30.7 (23/75) | 20.0 (15/75) | 55.2 (32/58) | 46.4 (32/69) | 9.0 (7/78) | |
| Any primary phenotype | 25.6 (67/262) | 38.6 (98/254) | 23.8 (65/273) | 64.8 (105/162) | 37.8 (87/230) | 11.9 (32/268) | 22.8 (62/272) |
Values are % (n/n).
Abbreviations: AL, afferent limb; IL, inlet.
We assessed how the primary phenotype transitioned to each of these subsequent phenotypes over time. Focusing on phenotypes previously known to have greatest clinical relevance,3,9,10 patients with primary AL involvement had a higher rate of transition to diffuse inflammation (38.1%; 5-year EFS 69.9%) and pouch-related fistulas (18.6%; 5-year EFS 79.7%). Patients with a primary diffuse inflammation had a 32.1% rate of subsequent AL involvement (5-year EFS 59.2%) and 20.2% pouch-related fistulas (5-year EFS 79.4%). Patients with primary pouch-related fistulas had 22.6% rate of transition to AL involvement (5-year EFS 73.8%) and 19.6% diffuse inflammation (5-year EFS 83.3%) (Figure 1Table 1, Figure S1).
Figure 1.
Kaplan-Meier curves to describe phenotype transitions of afferent limb (AL) involvement, diffuse inflammation of the pouch body, and pouch-related fistulas. For each primary phenotype, event-free survival (EFS) for a subsequent phenotype was estimated with Kaplan-Meier curve. EFS was assessed from the scope date when a primary phenotype was first identified to the date when a subsequent phenotype was described. The x-axis shows time (years) from the date when a primary phenotype was first identified to the date when a subsequent phenotype was described. The y-axis shows EFS. A, For a primary phenotype of AL involvement, EFS for a subsequent phenotype of diffuse inflammation of the pouch body. B, For a primary phenotype of AL involvement, EFS for a subsequent phenotype of pouch-related fistula. C, For a primary phenotype of diffuse inflammation of the pouch body, EFS for a subsequent phenotype of AL involvement. D, For a primary phenotype of diffuse inflammation of the pouch body, EFS for a subsequent phenotype of pouch-related fistula. E, For a primary phenotype of pouch-related fistula, EFS for a subsequent phenotype of AL involvement. F, For a primary phenotype of pouch-related fistula, EFS for a subsequent phenotype of diffuse inflammation of the pouch body.
Because our previous study showed that IL stenosis was associated with the risk of pouch excision,3 we also analyzed stenosis of the prepouch ileum. Our data showed that the overall rate of subsequent AL/IL stenoses was 13.2% in patients with any primary phenotype other than AL and IL involvements (Figure 2, Table S3). Among patients with subsequent AL/IL stenoses, the most common primary phenotype was pouch-related fistulas and 5-year EFS for AL/IL stenoses was 81.8% (Figure 2Table S3).
Figure 2.
Kaplan-Meier curves to describe phenotype transition to afferent limb (AL) or inlet (IL) stenoses. Primary AL involvement and IL involvement were excluded in this analysis. For each primary phenotype, event-free survival (EFS) for a subsequent AL/IL stenoses was estimated with Kaplan-Meier curve. EFS was assessed from the scope date when a primary phenotype was first identified to the date when a subsequent phenotype was described. The x-axis shows time (years) from the date when a primary phenotype was first identified to the date when a subsequent phenotype was described. The y-axis shows EFS. A, For a primary phenotype of diffuse inflammation of the pouch body, EFS for a subsequent phenotype of AL/IL stenoses. B, For a primary phenotype of focal inflammation of the pouch body, EFS for a subsequent phenotype of AL/IL stenoses. C, For a primary phenotype of cuffitis, EFS for a subsequent phenotype of AL/IL stenoses. D, For a primary phenotype of pouch-related fistula, EFS for a subsequent phenotype of AL/IL stenoses. E, For a primary phenotype of normal pouch, EFS for a subsequent phenotype of AL/IL stenoses.
We assessed the rate of pouch excision and found that patients who subsequently developed diffuse inflammation, pouch-related fistulas, and AL/IL stenoses had a significant increased risk of pouch excision (P < .001, P = .005, and P = .003, respectively) (Table 2). Patients with these subsequent phenotypes more frequently required postoperative treatments including oral mesalamine, immunomodulators, oral steroids, tumor necrosis factor α (TNF-α) antagonists, vedolizumab, or ustekinumab compared with patients without these subsequent phenotypes (Tables S4, S5, and S6). On the other hand, patients who achieved pouch normalization were less likely to use TNF-α antagonists or vedolizumab compared with those without a subsequent normal pouch (Table S7). The rate of pouch excision was almost 2 times lower in patients who achieved subsequent pouch normalization than patients who did not achieve pouch normalization, although this did not reach statistical significance (8.1% vs 15.7%; P = .15) (Table 2). When subsequent normalization was combined with subsequent focal inflammation, a phenotype with a favorable outcome,3 the result was not significant (Table 2). Five patients who achieved pouch normalization had pouch excision, and the most common reason was pouch dysfunction (3 patients), followed by the development of symptomatic refractory cuffitis (1 patient) and anal fissure (1 patient) after pouch normalization.
Table 2.
The rate of pouch excision in each subsequent phenotype among patients with any phenotypes.
| Subsequent AL Involvement (–) | Subsequent AL involvement (+) | P value |
|---|---|---|
| 11.3 (22/195) | 9.0 (6/67) | .819 |
| Subsequent IL Involvement (–) | Subsequent IL involvement (+) | P value |
|---|---|---|
| 9.0 (14/156) | 12.2 (12/98) | .404 |
| Subsequent AL/IL stenoses (–) | Subsequent AL/IL stenoses (+) | P value |
|---|---|---|
| 9.5 (25/263) | 27.5 (11/40) | .003 a |
| Subsequent diffuse inflammation (–) | Subsequent diffuse inflammation (+) | P value |
|---|---|---|
| 7.2 (15/208) | 26.2 (17/65) | <.001 a |
| Subsequent focal inflammation (–) | Subsequent focal inflammation (+) | P value |
|---|---|---|
| 10.5 (6/57) | 14.3 (15/105) | .627 |
| Subsequent cuffitis (–) | Subsequent cuffitis (+) | P value |
|---|---|---|
| 10.5 (15/143) | 14.9 (13/87) | .406 |
| Subsequent fistulas (–) | Subsequent fistulas (+) | P value |
|---|---|---|
| 9.3 (22/236) | 28.1 (9/32) | .005 a |
| Subsequent normal (–) | Subsequent normal (+) | P value |
|---|---|---|
| 15.7 (33/210) | 8.1 (5/62) | .148 |
| Subsequent normal/focal inflammation (–)b | Subsequent normal/focal inflammation (+)b | P value |
|---|---|---|
| 15.4 (4/26) | 12.1 (27/223) | .544 |
Values are% (n/n).
Abbreviations: AL, afferent limb; IL, inlet.
aValues indicate statistical significance (P < .05).
bSubsequent normal/focal inflammation was defined as the phenotype in which focal inflammation or normal pouch was developed on the last date of pouchoscopy in each patient.
Contributing Factors to Subsequent Phenotypes and Pouch Normalization
Given that patients who subsequently developed diffuse inflammation, pouch-related fistulas, and AL/IL stenosis were at a significantly increased risk of pouch loss, we assessed potential contributing factors to these subsequent phenotypes. We also assessed factors contributing to pouch normalization.
Subsequent diffuse inflammation of the pouch body
On univariate analysis, extensive colitis (E3) and primary AL involvement were significantly associated with subsequent diffuse inflammation (P = .019 and P = .004, respectively). On the other hand, age at diagnosis ≥18 years was negatively associated with subsequent diffuse inflammation (P = .023) (Table S4). On multivariable analysis including these variables, extensive colitis (E3) and primary AL involvement were significantly associated with subsequent diffuse inflammation (odds ratio [OR], 3.79; 95% CI, 1.09-13.2; and OR, 2.69; 95% CI, 1.36-5.31, respectively), whereas age at diagnosis ≥18 years was inversely associated with subsequent diffuse inflammation (OR, 0.47; 95% CI, 0.23-0.95) (Table 3).
Table 3.
Logistic regression models to assess contributing factors to subsequent phenotypes.
| Subsequent phenotype | n | Variables | Odds ratio (95% CI) | P value |
|---|---|---|---|---|
| Diffuse inflammation of the pouch body | 65 | Disease extent E3 | 3.79 (1.09-13.2) | .036 a |
| Age at diagnosis ≥18 y | 0.47 (0.23-0.95) | .036 a | ||
| Primary AL involvement | 2.69 (1.36-5.31) | .004 a | ||
| Pouch-related fistulas | 32 | Primary AL involvement | 2.35 (0.99-5.58) | .053 |
| Primary diffuse inflammation | 1.99 (0.87-4.56) | .10 | ||
| Primary focal inflammation | 0.34 (0.15-0.78) | .011 a | ||
| AL/IL stenosesb | 40 | Age at colectomy ≥18 y | 0.24 (0.09-0.63) | .0037 a |
| Preoperative anti-TNF-α drugs | 0.41 (0.18-0.91) | .029 a | ||
| Primary pouch-related fistulas | 2.09 (0.97-4.49) | .06 | ||
| Primary normal pouch | 0.19 (0.04-0.84) | .028 a | ||
| Normal pouch | 62 | Primary AL involvement | 0.72 (0.32-1.63) | .43 |
| Primary IL involvement | 0.68 (0.31-1.50) | .34 | ||
| Primary diffuse inflammation | 0.57 (0.26-1.22) | .15 | ||
| Primary pouch-related fistulas | 0.17 (0.06-0.48) | <.001 a |
Abbreviations: AL, afferent limb; CI, confidence interval; IL, inlet; TNF, tumor necrosis factor.
aValues indicate statistical significance (P < .05).
bFour factors showing P < .01 (Table S6) were preferentially selected to avoid overfitting.
Subsequent pouch-related fistulas
On univariate analysis, primary pouch phenotypes including AL involvement and diffuse inflammation were significantly associated with subsequent pouch-related fistulas (P = .026 and P = .008, respectively). Conversely, primary focal inflammation was negatively associated with subsequent pouch-related fistulas (P = .03) (Table S5). On multivariable analysis, primary focal inflammation was inversely associated with subsequent pouch-related fistulas (OR, 0.34; 95% CI, 0.15-0.78), whereas primary AL involvement increased the risk of subsequent pouch-related fistulas, although this was not statistically significant (OR, 2.35; 95% CI, 0.99-5.58) (Table 3).
Subsequent AL/IL stenoses
On univariate analysis, primary pouch-related fistulas and hand-sewn anastomosis were significantly associated with subsequent AL/IL stenoses (P = .002 and P = .029, respectively). On the other hand, age at colectomy ≥18 years, primary normal pouch, preoperative anti-TNF-α antagonists, and age at diagnosis ≥18 years were inversely associated with subsequent AL/IL stenoses (P = .001, P = .001, P = .005, and P = .037, respectively) (Table S6). Multivariable analysis including 4 variables with the smallest P values (P < .01) showed that age at colectomy ≥18 years, primary normal pouch, and preoperative anti-TNF-α antagonists were negatively associated with subsequent AL/IL stenoses (OR, 0.24; 95% CI, 0.09-0.63; OR, 0.19; 95% CI, 0.04-0.84; and OR, 0.41, 95% CI, 0.18-0.91, respectively). Primary pouch-related fistulas trended toward an increased risk of subsequent AL/IL stenoses (OR, 2.09; 95% CI, 0.97-4.49) (Table 3).
Pouch normalization
On univariate analysis, primary phenotypes including AL involvement, IL involvement, diffuse inflammation, and pouch-related fistulas were negatively associated with the subsequent pouch normalization (P = .046, P = .013, P = .02, and P < .001, respectively) (Table S7). There were no significant associations between pouch normalization and any pre- and postoperative treatments (Table S7). On multivariable analysis, pouch-related fistulas were inversely associated with pouch normalization (OR, 0.17; 95% CI, 0.06-0.48) (Table 3).
Discussion
We have shown that pouch phenotypes can change over time in patients with IBD and that in patients with pouch inflammation of various phenotypes, pouch normalization is feasible. Our data show that patients who subsequently developed diffuse inflammation of the pouch body, pouch-related fistulas, and AL/IL stenoses had a significantly increased risk of pouch loss and that pouch normalization decreased the risk of pouch removal.
In our recent work, we have assessed all available reports of pouchoscopies after ileostomy takedown and described 7 unique pouch phenotypes with different contributing factors and outcomes.3 We also found that patients with multiple unique but coexisting phenotypes had a significant risk of pouch excision, suggesting that the risk of pouch loss can change over time. In this analysis, if a phenotype was identified at least once in a patient’s pouchoscopies, the patient was included in the analysis for their respective phenotypic categories.3 Therefore, in complicated patients with multiple endoscopically defined phenotypes, there remain some unanswered questions, such as how one phenotype may change over time. In the present study, we clearly demonstrated that patients with any primary pouch phenotype can subsequently develop diffuse inflammation and these patients had a high risk of pouch removal. These data suggest that diffuse inflammation may be a phenotype that needs careful monitoring and intensive treatments.
A previous study demonstrated that patients with prepouch ileitis had a higher rate of CD-like complications such as perianal disease compared with patients with pouchitis.10 Consistent with these data, our study showed that patients with primary AL involvement often developed subsequent pouch-related fistulas (18.6%), and subsequent AL/IL stenoses were frequently observed in patients with primary pouch-related fistulas (25.0%). An interesting finding was that diffuse inflammation was the most common primary phenotype in patients with subsequent pouch-related fistula development. Conversely, primary focal inflammation significantly decreased the risk of subsequent pouch-related fistulas, suggesting that severe inflammatory burden in the pouch body may be linked to fistula formation in the J pouch. Given that primary AL involvement was an independent risk factor for subsequent diffuse inflammation and that diffuse inflammation appears to be associated with fistulizing disease, the combination of AL involvement, diffuse inflammation, and pouch-related fistulas may be a unique phenotype in patients who experience poor pouch outcomes.11 This pattern of initial diagnosis of AL involvement followed by development of fistulas and diffuse pouchitis development is informative, and further investigation of whether early biologic initiation for AL involvement may prevent subsequent development of fistulas or diffuse inflammation is warranted.
In patients with UC or CD, endoscopic healing is a well-validated goal to improve the long-term clinical outcomes.4 However, there are limited data to show the predictive value of endoscopic healing on pouch outcomes. Several studies focused on the endoscopic healing of the pouch.12-14 A retrospective, multicenter cohort study evaluating the efficacy of vedolizumab for chronic pouchitis or CD of the pouch defined achievement of completely normal mucosa as mucosal healing/endoscopic remission.14 They found that the proportion of patients who achieved mucosal healing was 13% at 3 months and 15% at 6 months after starting vedolizumab. Consistent with this finding, the rate of subsequent pouch normalization in patients with any primary phenotype was 22.8% in our analysis. We also found that the rate of pouch normalization was different for each pouch phenotype; the highest normalization rate was 24.8% in patients with primary focal inflammation and the lowest rate was 6.2% in patients with primary pouch-related fistulas. Indeed, multivariable analysis assessing contributing factors to subsequent pouch normalization showed that primary pouch-related fistula was a phenotype which made endoscopic healing of the pouch less likely. No previous study has shown an improvement in long-term pouch outcomes related to endoscopic normalization of the pouch. We demonstrated that patients who achieved pouch normalization less frequently used biologics and had a lower risk of pouch excision in comparison with patients without subsequent normal pouch, suggesting that patients who experienced pouch normalization may have milder endoscopic disease as a natural history (eg, focal inflammation of the pouch body). Pouch normalization is of clinical value to improve pouch outcomes, and appropriate management of pouch-related fistulas is a key point to achieve it.
A recent double-blind, randomized trial assessing the efficacy and safety of vedolizumab for chronic pouchitis15 used the modified Pouchitis Disease Activity Index,16 which is the scale based on clinical symptoms and endoscopic findings of pouchitis, although this instrument has not been fully validated. This study also included exploratory endpoints such as changes in the number of total erosions/ulcers of the pouch, Simple Endoscopic Score for Crohn’s Disease17 and Robarts Histopathology Index,18 and found that these endpoints were improved in vedolizumab-treated patients with chronic pouchitis, suggesting that endoscopic and histologic improvement are achievable goals.15 A recent study also uncovered that histologic activity in an endoscopically normal-appearing pouch was significantly associated with the risk of acute pouchitis.19 Therefore, future studies are warranted to understand whether improvement or normalization in endoscopic or histologic activity may reduce the risk of poor pouch outcomes and are an ideal therapeutic endpoint for both clinical trials and patient care in pouchitis.
We showed that ages at diagnosis or colectomy ≥18 years were inversely associated with subsequent diffuse inflammation or AL/IL stenoses, suggesting that patients with pediatric-onset IBD would have a higher risk of subsequent pouch phenotypes with poor prognosis in comparison with patients with adult-onset IBD. A recent population-based study demonstrated that patients with pediatric-onset IBD more often presented with extensive disease localization and exposed to systemic steroids, thiopurines, and biologics than patients with adult-onset IBD, suggesting a more severe disease course in pediatric-onset IBD than in adult-onset IBD.20 Our data also showed that greater disease extent (E3) was a significant predictor for subsequent diffuse pouch inflammation. All these findings suggest that if patients have more clinically complex or resistant disease before surgery, they may likely develop subsequent pouch phenotypes with poorer prognoses. However, given that several studies showed no significant difference in the rate of pouch failure between pediatric and adult subjects,21,22 the true risk of pouch loss in patients with pediatric-onset IBD remains to be elucidated.
There are multiple strengths and several limitations to this study. A significant strength was that this study included a large number of patients with data regarding pouchoscopy, which was performed by experienced endoscopists at a single tertiary/quaternary IBD center. It was also a strength that pouchoscopy was conducted based on a standard operating protocol, and a previously published endoscopic phenotype classification of the pouch3 was used in this study. However, we acknowledge that it was also a limitation that the study was conducted at a single center, which may have biased the results. Additionally, the retrospective design limited our analysis to those patients who underwent pouchoscopies, which in many cases were indicated because of their symptoms suggestive of pouchitis. Given that the frequency of follow-up scopes may depend on clinical symptoms, patients who achieved pouch normalization may be less likely to have follow-up pouchoscopies, and this would affect our results regarding the transition to subsequent inflammatory phenotypes in patients with primary normal phenotype. Thus, the severity of clinical symptoms based on our classification is the subject of our future studies. Further, the likelihood of transition to each phenotype may be affected by postoperative variables, particularly treatments. We have included postoperative treatment data with univariate analysis to assess factors contributing to subsequent phenotypes with poor outcomes (eg, diffuse inflammation, AL/IL stenoses, pouch-related fistulas) as well as to pouch normalization. We found that patients who developed the phenotypes with poor outcomes were more likely to be treated with advanced therapies, whereas patients who achieved normalization of the pouch were less likely to use biologics, suggesting that postoperative therapies are likely driven by severity of phenotypes and that endoscopic phenotype changes would be less likely to be attributed to the postoperative treatments. Finally, our analysis did not necessarily indicate the transition of a single phenotype, because in some cases a subsequent phenotype was simply added to the pre-existing primary phenotype. Given that the number of events in each analysis regarding phenotype transition was relatively small, prospective studies are needed to validate our findings.
Conclusions
We demonstrated that pouch phenotypes can change over time and that subsequent development of diffuse inflammation, pouch-related fistulas, and AL/IL stenoses significantly worsens pouch outcomes. Our analysis also showed that pouch normalization is possible and is associated with favorable pouch outcomes. Further investigations are needed to determine if patients with these subsequent phenotypes with poor prognosis require intensive treatments and whether pouch endoscopic normalization should be a target of treatments for IBD patients with IPAA.
Supplementary Data
Supplementary data is available at Inflammatory Bowel Diseases online.
Contributor Information
Shintaro Akiyama, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Jacob E Ollech, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Nathaniel A Cohen, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Cindy Traboulsi, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Victoria Rai, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Laura R Glick, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Yangtian Yi, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Joseph Runde, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Russell D Cohen, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Kinga B Skowron Olortegui, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Roger D Hurst, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Konstantin Umanskiy, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Benjamin D Shogan, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Neil H Hyman, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Michele A Rubin, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Sushila R Dalal, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Atsushi Sakuraba, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Joel Pekow, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Eugene B Chang, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
David T Rubin, University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, IL, USA.
Author Contributions
Study concept and design: S.A., D.T.R. Acquisition of data: S.A., J.E.O., C.T., V.R., Y.Y., L.R.G., J.R., R.D.C., K.B.S., R.D.H., K.U., B.D.S., N.H.H., M.A.R., S.R.D., A.S., J.P., D.T.R. Analysis and interpretation of data: S.A., N.A.C., D.T.R. Drafting of manuscript: S.A., N.A.C., C.T., V.R., D.T.R. Critical revision of manuscript: S.A., N.A.C., C.T., V.R., D.T.R.
Funding
Funding was in part provided by National Institute of Diabetes and Digestive and Kidney Diseases P30 DK42086, National Institute of Diabetes and Digestive and Kidney Diseases RC2 DK122394, and the GI Research Foundation of Chicago.
Conflicts of Interest
N.A.C. has served as a consultant for Iterative Health, Takeda, and Seres Pharmaceuticals; and received travel support from Pfizer. R.D.C. has served on the speakers bureau for AbbVie, BMS, and Takeda; and as a consultant for AbbVie, BMS, Eli Lilly, Genentech, Gilead Sciences, Hoffman La-Roche, Janssen, Pfizer, Takeda, and UCB Pharma. M.A.R. has served as a consultant for Pfizer. S.R.D. has served as a consultant for Pfizer; and on the speakers bureau for AbbVie. J.P. has received grant support from AbbVie and Takeda; and has served as a consultant for Veraste and CVS Caremark; and on the advisory board for Takeda, Janssen, and Pfizer. E.B.C. is the founder and chief medical officer of AVnovum Therapeutics. D.T.R. has received grant support from Takeda; and served as a consultant for AbbVie, AbGenomics, Arena Pharmaceuticals, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Syneos, Dizal Pharmaceuticals, Genentech/Roche, Gilead Sciences, Ichnos Sciences S.A., InDex Pharmaceuticals, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Laboratories, Reistone, Takeda, and Techlab Inc.
Data Availability
The data underlying this article will be shared upon request from the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data underlying this article will be shared upon request from the corresponding author.